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TWI295670B - Vanilloid receptor ligands and their use in treatments - Google Patents

Vanilloid receptor ligands and their use in treatments Download PDF

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TWI295670B
TWI295670B TW094104222A TW94104222A TWI295670B TW I295670 B TWI295670 B TW I295670B TW 094104222 A TW094104222 A TW 094104222A TW 94104222 A TW94104222 A TW 94104222A TW I295670 B TWI295670 B TW I295670B
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ethyl
fluorophenyl
oxy
pyrimidinyloxy
mmol
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TW094104222A
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Chinese (zh)
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TW200534858A (en
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Hui Ling Wang
Chenera Balan
Elizabeth M Doherty
James R Falsey
Vijay Keshav Gore
Jodie Katon
Mark H Norman
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Amgen Inc
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Abstract

Pyrimidine ethers and compositions containing them, for the treatment of acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritus, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders.

Description

1295670 九、發明說明： 本申請請求2004年2月11曰建檔的美國臨時申請號碼 60/543,896的優點之專利，其並列於本文做參考。 【發明所屬之技術領域】 本發明包括可用來治療諸如類香草精受體媒介的疾病和 其他病症的疾病之新一類化合物，諸如涉及感覺神經功能 的發炎性或神經病變性疼痛與疾病，諸如氣喘、類風濕性 關節炎、骨關節炎、發炎性腸疾、尿失禁、偏頭痛與牛皮 癬。 【先前技術】 第一型類香草精受體（VR1)為辣椒的活性成分-辣椒素的 分子目標。Julius等已提出VR1分子選殖的報告（Caterina 等，1997)。VR1為非選擇性陽離子通道，其會受一系列不 同的刺激所活化或敏感化，包括辣椒素與樹脂毒素（外源性 活化劑）、熱與酸刺激以及脂質雙層代謝的產物-大麻素 (Premkumer等，2000 ; Szabo等，2000 ; Gauldie等，2001 ; Olah等，2001)與脂質氧化酶代謝物（Hwang等，2000)。VR1 在大鼠、小鼠和人類（Onozawa等，2000 ; Mezey等，2000 ; Helliwell等，1998 ; Cortright等，2001)的初級感覺神經元 中（Caterina等，1997)高度表現。這些感覺神經元使神經分 佈於很多内臟器官，包括真皮、骨骼、膀胱、腸胃道與肺 臟；VR1也在其他神經元及非神經元組織表現，包括但不 限於CNS細胞核、腎臟、胃與T細胞（Nozawa等，2001 ; Yiangou等，2001 ; Birder等，2001)。我們推測，在這些不 99461.doc 1295670 同的細胞和器官中的表現可能對它們的基礎性質，諸如細 胞訊號產生與細胞分裂有所貢獻。 在VR1的分子選殖之前，利用辣椒素的實驗顯示有能夠 提高人類、大鼠與小鼠的感覺神經元活性之辣撤素敏感性 受體存在（Holzer，1991 ; Dray，1992 ; Szallasi 與 Blumberg， 1996、1999)。藉由辣椒素對人體急性活化的結果是會引起 注射位置的疼痛，而且對於其他物種會產生增高的對於感 覺刺激之行為敏感性（Szallasi與Blumberg，1999)。把辣椒 素抹在人的皮膚會造成疼痛反應，它的特徵不僅是在施用 的位置感受到熱與疼痛，還包括大面積的痛覺過敏與異常 疼痛-測試人體的神經病變性疼痛病情的兩個主要症狀 (Holzer，1991)。總括來說，提高的VR1活性似乎在疼痛病 隋的成立和維持上扮》貝明顯的角色。經顯示，局部或皮内 注射辣椒素也會產生局部的血管擴張和水腫（82&11&3丨與 Blumberg，1999; Singh等，2001)。此一證據顯示，辣椒素 經由其活化VR1會調控感覺神經的傳入和輸出。因而，可 藉由影響類香草精受體功能的分子來修飾涉及疾病的感覺 神經，以提高或減低感覺神經的活性。 經顯不，VR1基因受破壞的小鼠對於熱和酸刺激的感覺 敏感性降低（Caterina等，2000)。此結果也支持VR1不僅對 於疼痛反應的產生有所貢獻，還包括對於感覺神經基礎活 性的維持。這個證據和展現涉及疾病的辣椒素敏感性神經 之研九、、Ό果致。藉由持續的辣椒素刺激，會使人類和 99461.doc 1295670 其他物種的初級感覺神經鈍化。此一範例造成受體活化誘 發的初級感覺神經之去敏感化·這種在活體内的感覺神經 活性的減低會讓受測者對於後續的疼痛刺激較不敏感。就 此方面而言，辣椒素和樹脂毒素（VR1的外源性活化劑）會造 成去敏感化；而且，人們也利用它們做為很多活體内疾病 模式的概念研究之證明（Holzer，1991; Dray，1992; Szallasi 與 Blumberg，1999)。1295670 IX. INSTRUCTIONS: This application claims the benefit of the benefit of U.S. Provisional Application Serial No. 60/543,896, filed on Feb. FIELD OF THE INVENTION The present invention encompasses a new class of compounds that can be used to treat diseases such as vanilloid receptor-mediated diseases and other conditions, such as inflammatory or neuropathic pain and diseases involving sensory nerve function, such as asthma, Rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, urinary incontinence, migraine and psoriasis. [Prior Art] The first type of vanillin receptor (VR1) is the molecular target of capsaicin, the active ingredient of capsicum. Julius et al. have reported the VR1 molecular selection (Caterina et al., 1997). VR1 is a non-selective cation channel that is activated or sensitized by a range of different stimuli, including capsaicin and resin toxins (exogenous activators), heat and acid stimulation, and products of lipid bilayer metabolism - cannabinoids. (Premkumer et al, 2000; Szabo et al, 2000; Gauldie et al, 2001; Olah et al, 2001) and lipid oxidase metabolites (Hwang et al, 2000). VR1 is highly expressed in primary sensory neurons (Caterina et al., 1997) in rats, mice, and humans (Onozawa et al, 2000; Mezey et al, 2000; Helliwell et al, 1998; Cortright et al, 2001). These sensory neurons distribute nerves in many internal organs, including the dermis, bones, bladder, gastrointestinal tract, and lungs; VR1 is also expressed in other neuronal and non-neuronal tissues, including but not limited to CNS nuclei, kidneys, stomach, and T. Cells (Nozawa et al, 2001; Yiangou et al, 2001; Birder et al, 2001). We hypothesize that performance in these cells and organs that are not 99461.doc 1295670 may contribute to their underlying properties, such as cell signal generation and cell division. Prior to the molecular selection of VR1, experiments with capsaicin showed the presence of a succulent sensitive receptor that enhances sensory neuronal activity in humans, rats, and mice (Holzer, 1991; Dray, 1992; Szallasi and Blumberg) , 1996, 1999). As a result of acute activation of capsaicin in humans, it causes pain in the injection site and, for other species, produces increased sensitivity to sensory stimuli (Szallasi and Blumberg, 1999). Applying capsaicin to human skin can cause painful reactions. It is characterized not only by heat and pain at the site of application, but also by extensive hyperalgesia and abnormal pain - two major tests for neuropathic pain in the human body. Symptoms (Holzer, 1991). In summary, the increased VR1 activity appears to play a prominent role in the establishment and maintenance of painful illnesses. Local or intradermal injection of capsaicin has also been shown to cause localized vasodilation and edema (82 & 11 & 3 & Blumberg, 1999; Singh et al, 2001). This evidence suggests that capsaicin, through its activation of VR1, regulates the afferent and output of sensory nerves. Thus, the sensory nerves involved in the disease can be modified by molecules that affect the function of the vanilloid receptor to increase or decrease the activity of the sensory nerves. It has been shown that mice with VR1 gene disruption have reduced sensitivity to heat and acid stimuli (Caterina et al., 2000). This result also supports that VR1 not only contributes to the development of pain response, but also to the maintenance of sensory nerve base activity. This evidence and the discovery of capsaicin-sensitive nerves involved in the disease are studied. By sustained capsaicin stimulation, the primary sensory nerves of humans and other species of 99461.doc 1295670 are inactivated. This paradigm causes desensitization of the primary sensory nerves induced by receptor activation. This decrease in sensory neuronal activity in vivo may make the subject less sensitive to subsequent painful stimuli. In this respect, capsaicin and resin toxins (exogenous activators of VR1) cause desensitization; moreover, they are used as proof of conceptual studies of many in vivo disease patterns (Holzer, 1991; Dray, 1992; Szallasi and Blumberg, 1999).

BibliographyBibliography

Birder-LA. Kanai-AJ. de-Groat-WC. Kiss-S. Nealen-ML. Burke-NE.-Dineley-KE. Watkins-S. Reynolds-IJ. Caterina-MJ. (2001) Vanilloid receptor expression suggests a sensory role for urinary bladder epithelial cells. PNAS 98:23: 13396-13401.Birder-LA. Kanai-AJ. de-Groat-WC. Kiss-S. Nealen-ML. Burke-NE.-Dineley-KE. Watkins-S. Reynolds-IJ. Caterina-MJ. (2001) Vanilloid receptor expression suggests a sensory role for urinary bladder epithelial cells. PNAS 98:23: 13396-13401.

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Treanor-J. Curran-E. (2000) Inflammation-induced upregulation of VR1 in -rat spinal cord and DRG correlates with enhanced nociceptive processing. Society for Neuroscience Abstracts 26:1-2: 632.15. 【發明内容】 本發明包括可用來治療諸如類香草精受體媒介的疾病和 其他病症的疾病之新一類化合物，諸如涉及感覺神經功能 的發炎性或神經病變性疼痛與疾病，諸如氣喘、類風濕性 關節炎、骨關節炎、發炎性腸疾、尿失禁、偏頭痛與牛皮 癬。特別是本發明化合物可用來治療急性、發炎性，與神 經病變性疼痛、牙痛、一般性頭痛、偏頭痛、聚叢性頭痛、 混合性血管與非血管症候群、緊張性頭痛、一般性發炎、 關節炎、風濕病、骨關節炎、發炎性腸疾、焦慮、憂鬱症、 發炎性眼疾、發炎性或不穩定性膀胱病症、牛皮癬、發炎 性成分引起的皮膚不適、慢性發炎性病情、發炎性疼痛與 相關的痛覺過敏與異常疼痛、神經病變性疼痛與相關的痛 覺過敏與異常疼痛、糖尿病神經病變性疼痛、灼熱痛、交 99461.doc 1295670 感神經所致的疼痛、去傳入神經症候群、氣喘、上皮細胞 組織損害或功能障礙、單純泡疹、呼吸道、泌尿生殖系統、 胃腸或血管區域的臟器蠕動失調、傷口、灼傷、過敏性皮 膚反應、搔療症、白斑病、一般性胃腸病症、胃潰癌、十 二指腸潰瘍、腹瀉、致壞死劑造成的胃損傷、頭髮生長、 血管運動或過敏性鼻炎、支氣管病症或膀胱病症。據此， 本發明也包括含有治療類香草精受體媒介的疾病之化合 物、方法之醫藥組合物，此類疾病諸如發炎性或神經病變 性疼痛、氣喘、類風濕性關節炎、骨關節炎、發炎性腸疾、-尿失禁、偏頭痛與牛皮癬疾病等，利用本發明化合物和組 合物，以及有用的中間體和方法來製備本發明化合物。 本發明化合物係以下列的一般結構表示：Treanor-J. Curran-E. (2000) Inflammation-induced upregulation of VR1 in -rat spinal cord and DRG correlates with enhanced nociceptive processing. Society for Neuroscience Abstracts 26:1-2: 632.15. [Summary of the Invention] The present invention includes A new class of compounds for the treatment of diseases such as vanilloid receptor-mediated diseases and other conditions, such as inflammatory or neuropathic pain and diseases involving sensory nerve function, such as asthma, rheumatoid arthritis, osteoarthritis, inflammation Sexual bowel disease, urinary incontinence, migraine and psoriasis. In particular, the compounds of the invention are useful for the treatment of acute, inflammatory, neuropathic pain, toothache, general headache, migraine, clustered headache, mixed vascular and non-vascular syndrome, tension headache, general inflammation, arthritis , rheumatism, osteoarthritis, inflammatory bowel disease, anxiety, depression, inflammatory eye disease, inflammatory or unstable bladder disease, psoriasis, skin irritation caused by inflammatory ingredients, chronic inflammatory conditions, inflammatory pain and Related Hyperalgesia and Abnormal Pain, Neuropathic Pain and Related Hyperalgesia and Abnormal Pain, Diabetic Neuropathic Pain, Burning Pain, Intercourse 99461.doc 1295670 Sensory Pain, De-Afferent Neurological Syndrome, Asthma, Epithelial Cells Tissue damage or dysfunction, simple herpes, respiratory tract, genitourinary system, gastrointestinal motility disorders in the gastrointestinal or vascular areas, wounds, burns, allergic skin reactions, sputum therapy, leukoplakia, general gastrointestinal disorders, gastric ulceration , duodenal ulcer, diarrhea, stomach damage caused by necrosis, hair Long, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders. Accordingly, the present invention also encompasses pharmaceutical compositions, such as inflammatory or neuropathic pain, asthma, rheumatoid arthritis, osteoarthritis, inflammation, which comprise a disease-treating agent for a vanilloid-receptive agent. Sexual enteropathy, urinary incontinence, migraine and psoriasis diseases, etc., using the compounds and compositions of the invention, as well as useful intermediates and methods, are useful in the preparation of the compounds of the invention. The compounds of the invention are represented by the following general structure:

或其醫藥可接受的鹽，其中R1、R2、R3、R3,、R4與χ之定 義如下。 前述說明僅將本發明的某些方面做摘要，無論如何並 非’或者是被理解為是在限制本發明。所有的申請、專利 申請和其他在本文中所引用的出版品，都全文並列於本文 供參考。 【實施方式】 99461.doc -12· 1295670 本發明一方面是有關具下列一般結構的化合物：Or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R3, R4 and hydrazine are as defined below. The foregoing description is merely illustrative of certain aspects of the invention, and is not intended to All applications, patent applications, and other publications cited herein are hereby incorporated by reference in their entirety. [Embodiment] 99461.doc -12· 1295670 One aspect of the invention relates to a compound having the following general structure:

或醫藥可接受的鹽，其中： X為N或C ;其中，當X為n時，〆代表單鍵，而當X為c 時，則^代表單或雙鍵； R為飽和、部分飽和或不飽和的包含1、2、3或4個選自N、 〇與S的原子之5-、6-或7·員環，其中，該環的碳原子係經〇、 1或2個氧基所取代，而該環係經〇、1、2或3個選自下列之 取代基所取代：Cw烷基、Cm鹵烷基、齒基、氰基、硝基、 -C(=0)Rb、_C(=0)0Rb、_C(=0)NRaRa、-C(=NRa) NRaRa、 -ORa、-0C( = 0)Rb、-0C(=0)NRaRa、.0C(=0)N(Ra)S(=0)2Rb、 _〇C2-6 烷基 NRaRa、_〇C2_6 烷基 〇Ra、-SRa、-S(=0)Rb、 -S(=0)2Rb、-S( = 0)2NRaRa、-S(=0)2N(Ra)C(=0)Rb、 -S(=0)2N(Ra)C(=0)0Rb 、 -S(=0)2N(Ra)C(=0)NRaRa 、 -NRaRa、-N(Ra)C(=0)Ra、-N(Ra)C(=0)0Rb、-N(Ra)C(=〇) NRaRa> -N(Ra)C(=NRa)NRaRa> -N(Ra)S(=0)2Rb> -N(Ra)S(=〇)2 NRaRa、-NRaC2_6烷基 NRaRa與_NRaC2_6烷基 〇Ra，或 R1 為經 1、2或3個選自下列之取代基所取代的苯基·· Cl-8烷基、Cw 鹵烷基、鹵基、氰基、硝基、-C(=0)Rb、-C(=0)〇Rb、 9946l.doc -13· 1295670 -C(=0)NRaRa、-C(=NRa)NRaRa、-ORa、-0C(=0)Rb、-0C(=0) NRaRa、·0(：(=0)Ν(Ι^)8(=0)2Γ^、-OC2.6烷基NRaRa、-OC2.6 烷基 ORa、-SRa、-S(=0)Rb、-S(=0)2Rb、-S(=0)2NRaRa、 -S(=0)2N(Ra)C(=0)Rb 、 -S(=0)2N(Ra)C(=0) ORb 、 -S(=0)2N(Ra)C(=0)NRaRa、-NRaRa、-N(Ra)C(=0)Rb、 -N(Ra)C(=0)0Rb、-N(Ra)C(=0)NRaRa、-N(Ra)C(=NRa) NRaRa、-N(Ra)S(=0)2Rb、-N(Ra)S(=0)2NRaRa 、-NRaC2-6 烷基 NRaRa與-NRaC2_6烷基 ORa ; R2為獨立的部分飽和或不飽和的包含1、2、3或4個選自 N、Ο與S的原子之8-、9-、10-或11-員雙環，其中該環的碳 原子係經0、1或2個氧基所取代，而該環係經0、1、2或3 • 個選自下列之取代基所取代：C 1 烧基、C 1 鹵烧基、鹵基、 : 氰基、硝基、-C(=0)Rb、-C(=0)0Rb、-C(=0)NRaRa、-C(=NRa) - NRaRa、-ORa、_0C(=0)Rb、-0C(=0)NRaRa、_0C(=0)N(Ra)S (=0)2Rb、-OC2_6 烷基 NRaRa、-OC2-6 烷基 ORa、-SRa、 -S(=0)Rb、_S(=0)2Rb、-S(=0)2NRaRa、-S(=0)2N(Ra)C(=0) • Rb、-S(=0)2N(Ra)C(=0)0Rb、-S(=0)2N(Ra)C(=0)NRaRa、 -NRaRa、-N(Ra)C(=0)Rb、-N(Ra)C(=0)0Rb、-N(Ra)C(=0) NRaRa、-N(Ra)C(=NRa)NRaRa、-N(Ra)S(=0)2Rb、-N(Ra)S(=0)2 NRaRa、-NRaC2.6烷基 NRaRa與-NRaC2_6烷基 ORa ; ^ R3與R3、獨立的，在個別實例中，H、甲基或乙基；或 - R3與R3’一起可能合併其所附接之碳原子而形成環丙基； R4為Η或甲基；Or a pharmaceutically acceptable salt, wherein: X is N or C; wherein, when X is n, 〆 represents a single bond, and when X is c, then ^ represents a single or double bond; R is saturated, partially saturated or Unsaturated 5-, 6- or 7-membered ring containing 1, 2, 3 or 4 atoms selected from N, fluorene and S, wherein the ring has a carbon atom which is fluorene, 1 or 2 oxy groups. Substituted, and the ring is substituted with 1, 2 or 3 substituents selected from the group consisting of Cw alkyl, Cm haloalkyl, dentyl, cyano, nitro, -C(=0)Rb , _C(=0)0Rb, _C(=0)NRaRa, -C(=NRa) NRaRa, -ORa, -0C(=0)Rb, -0C(=0)NRaRa, .0C(=0)N(( Ra)S(=0)2Rb, _〇C2-6 alkyl NRaRa, _〇C2_6 alkyl〇Ra, -SRa, -S(=0)Rb, -S(=0)2Rb, -S( = 0 2NRaRa, -S(=0)2N(Ra)C(=0)Rb, -S(=0)2N(Ra)C(=0)0Rb, -S(=0)2N(Ra)C(= 0) NRaRa, -NRaRa, -N(Ra)C(=0)Ra, -N(Ra)C(=0)0Rb, -N(Ra)C(=〇)NRaRa> -N(Ra)C( =NRa)NRaRa>-N(Ra)S(=0)2Rb> -N(Ra)S(=〇)2 NRaRa, -NRaC2_6 alkyl NRaRa and _NRaC2_6 alkyl 〇Ra, or R1 is 1, 2 Or a phenyl··Cl-8 alkyl group substituted with a substituent selected from the group consisting of Cw haloalkyl, Halo, cyano, nitro, -C(=0)Rb, -C(=0)〇Rb, 9946l.doc -13· 1295670 -C(=0)NRaRa, -C(=NRa)NRaRa,- ORa, -0C(=0)Rb, -0C(=0) NRaRa, ·0(:(=0)Ν(Ι^)8(=0)2Γ^, -OC2.6 alkyl NRaRa, -OC2. 6 alkyl ORa, -SRa, -S(=0)Rb, -S(=0)2Rb, -S(=0)2NRaRa, -S(=0)2N(Ra)C(=0)Rb, - S(=0)2N(Ra)C(=0) ORb, -S(=0)2N(Ra)C(=0)NRaRa, -NRaRa, -N(Ra)C(=0)Rb, -N (Ra)C(=0)0Rb, -N(Ra)C(=0)NRaRa, -N(Ra)C(=NRa) NRaRa, -N(Ra)S(=0)2Rb, -N(Ra S(=0)2NRaRa, -NRaC2-6 alkyl NRaRa and -NRaC2_6 alkyl ORa; R2 is independently partially saturated or unsaturated containing 1, 2, 3 or 4 atoms selected from N, Ο and S An 8-, 9-, 10- or 11-membered bicyclic ring wherein the ring carbon atom is substituted by 0, 1 or 2 oxy groups, and the ring system is selected from 0, 1, 2 or 3 Substituted by the following substituents: C 1 alkyl, C 1 halo, halo, cyano, nitro, -C(=0)Rb, -C(=0)0Rb, -C(=0) NRaRa, -C(=NRa) - NRaRa, -ORa,_0C(=0)Rb, -0C(=0)NRaRa,_0C(=0)N(Ra)S (=0)2Rb, -OC2_6 alkyl NRaRa , -OC2-6 alkyl ORa, -SRa, -S(=0)Rb, _S(=0)2Rb -S(=0)2NRaRa, -S(=0)2N(Ra)C(=0) • Rb, -S(=0)2N(Ra)C(=0)0Rb, -S(=0)2N (Ra)C(=0)NRaRa, -NRaRa, -N(Ra)C(=0)Rb, -N(Ra)C(=0)0Rb, -N(Ra)C(=0)NRaRa,- N(Ra)C(=NRa)NRaRa, -N(Ra)S(=0)2Rb, -N(Ra)S(=0)2 NRaRa, -NRaC2.6 alkyl NRaRa and -NRaC2_6 alkyl ORa; ^ R3 and R3, independently, in individual instances, H, methyl or ethyl; or - R3 together with R3' may combine the carbon atom to which they are attached to form a cyclopropyl group; R4 is hydrazine or methyl;

Ra為獨立的，在個別實例中，Η或Rb ;而 99461.doc -14- 1295670 以為獨立的，在個別實例中，苯基、苄基或cN6烷基，該 笨基、苄基與(：1-6烷基係經〇、1、2或3個選自下列之取代基 所取代：鹵基、Cw烷基、Cw鹵烷基、-OCu烧基、-丽2、 •NHCw烷基、-N(Cl 4烷基）Ci-4烷基。 在另一個具體實施例中，加上任何一個上述與下述的具 體實施例，本發明具有下列的一般結構：Ra is independent, in individual instances, Η or Rb; and 99461.doc -14-1295670 is considered to be independent, in individual instances, phenyl, benzyl or cN6 alkyl, the stupid, benzyl and (: The 1-6 alkyl group is substituted with hydrazine, 1, 2 or 3 substituents selected from the group consisting of halo, Cw alkyl, Cw haloalkyl, -OCu alkyl, -Li 2, •NHCw alkyl, -N(Cl 4 alkyl)Ci-4alkyl. In another embodiment, plus any of the specific embodiments described above and below, the invention has the following general structure:

或其任何醫藥可接受的鹽，其中： R為獨立的部分飽和或不飽和的包含1、2、3或4個選自 N、〇與S的原子之8·、9-、10-或11-員雙環，其中該環的碳 原子係經0、1或2個氧基所取代，而該環係經〇、丨、2或3 個選自下列之取代基所取代：Cl-8烷基、c1-4_烷基、鹵基、 氰基、硝基、_C(=〇)Rb、_C(=0)0Rb、-C(=0)NRaRa、-C(=NRa) NR Ra、-〇Ra、、〇c(=〇)Rb、_〇c(=〇)NRaRa、-〇C(=〇)N(Ra) S(=〇)2Rb、-〇C2.6 烷基 NRaRa、-OC2-6 烷基 〇Ra、-SRa、 'S(-〇)Rb , .S(=0)2Rb > -S(=0)2NRaRa > -S(=0)2N(Ra)C(=0) b R、-S(=〇)2N(Ra)C(=0)ORb、-S(=0)2N(Ra)C( = 0)NRaRa、 -NRaRa , .N(Ra)C(=0)Rb ^ -N(Ra)C(-0) 〇Rb > -N(Ra)C(=0) NRaRa、-N(R，c(=NRa)NRaRa、-N(Ra)S (=0)2Rb、-N(Ra)S (=0)2NRaRa、-NRaC2_6 烷基 NRaRa 與-NRaC2_6 烷基 〇Ra ; 99461.doc' (s 1295670 R4為Η或甲基； R5為獨立的，在個別實例中，選自Η、Cu烷基、Cw鹵 烷基、鹵基、氰基、硝基、-(:(=0)1115、-C(=0)0Rb、 -C(=0)NRaRa、-C(=NRa)NRaRa、-〇Ra、-0C(=0)Rb、_0C(=0) NRaRa、-0C(=0)N(Ra)S(=0)2Rb、-〇C2-6烷基NRaRa、-OC2-6 烷基 ORa、-SRa、-S(=0)Rb、-S(=0)2Rb、-S(=0)2NRaRa、 歸S(=0)2N(Ra)C(=0)Rb、-S(=0)2N(Ra)C(=0)0Rb、-S(=0)2N (Ra)C( = 〇)NRaRa、-NRaRa、-N(Ra)C(=0)Rb、-N(Ra)C(=0) 〇Rb、_N(Ra)C(=0)NRaRa、-N(Ra)C (=NRa)NRaRa、-N(Ra)S (=0)2Rb、-N(Ra)S(=0)2NRaRa、-NRaC2.6 烷基 NRaRa 與 -NRaC2_6烷基 〇Ra ;Or any pharmaceutically acceptable salt thereof, wherein: R is independently partially saturated or unsaturated, comprising 8, 2, 10 or 4 of the atoms selected from the group consisting of N, fluorene and S. a bicyclic ring wherein the carbon atom of the ring is substituted by 0, 1 or 2 oxy groups, and the ring system is substituted with hydrazine, hydrazine, 2 or 3 substituents selected from the group consisting of: Cl-8 alkyl , c1-4_alkyl, halo, cyano, nitro, _C(=〇)Rb, _C(=0)0Rb, -C(=0)NRaRa, -C(=NRa) NR Ra, -〇 Ra, 〇c(=〇)Rb, _〇c(=〇)NRaRa, -〇C(=〇)N(Ra) S(=〇)2Rb, -〇C2.6 alkyl NRaRa, -OC2- 6 alkyl hydrazine Ra, -SRa, 'S(-〇) Rb , .S(=0)2Rb > -S(=0)2NRaRa > -S(=0)2N(Ra)C(=0) b R, -S(=〇)2N(Ra)C(=0)ORb, -S(=0)2N(Ra)C( = 0)NRaRa, -NRaRa, .N(Ra)C(=0) Rb ^ -N(Ra)C(-0) 〇Rb > -N(Ra)C(=0) NRaRa, -N(R,c(=NRa)NRaRa, -N(Ra)S (=0) 2Rb, -N(Ra)S (=0)2NRaRa, -NRaC2_6 alkyl NRaRa and -NRaC2_6 alkyl 〇Ra; 99461.doc' (s 1295670 R4 is oxime or methyl; R5 is independent, in individual instances , selected from hydrazine, Cu alkyl, Cw haloalkyl, halo, cyano, nitro, -(:(=0)1115 , -C(=0)0Rb, -C(=0)NRaRa, -C(=NRa)NRaRa, -〇Ra, -0C(=0)Rb,_0C(=0) NRaRa, -0C(=0) N(Ra)S(=0)2Rb, -〇C2-6 alkyl NRaRa, -OC2-6 alkyl ORa, -SRa, -S(=0)Rb, -S(=0)2Rb, -S( =0) 2NRaRa, return S(=0)2N(Ra)C(=0)Rb, -S(=0)2N(Ra)C(=0)0Rb, -S(=0)2N (Ra)C ( = 〇)NRaRa, -NRaRa, -N(Ra)C(=0)Rb, -N(Ra)C(=0) 〇Rb, _N(Ra)C(=0)NRaRa, -N(Ra) C (=NRa)NRaRa, -N(Ra)S (=0)2Rb, -N(Ra)S(=0)2NRaRa, -NRaC2.6 alkyl NRaRa and -NRaC2_6 alkyl〇Ra;

Ra為獨立的，在個別實例中，H或Rb ;而 1^為獨立的，在個別實例中，苯基、苄基或C1-6烷基，該 本基、亨基與C1 _6烧基係經〇、1、2或3個選自下列之取代基 所取代：鹵基、Cw烷基、Cu鹵烷基、-OCw烷基、-NH2、 -NHCK4烷基、-ΝβΜ烷基）Cb4烷基。 在另一個具體實施例中，加上任何一個上述與下述的具 體實施例，本發明具有下列的一般結構：Ra is independent, in individual instances, H or Rb; and 1^ is independent, in individual instances, phenyl, benzyl or C1-6 alkyl, the base, Henry and C1 _6 alkyl Substituted by 1, 2 or 3 substituents selected from the group consisting of halo, Cw alkyl, Cu haloalkyl, -OCw alkyl, -NH2, -NHCK4 alkyl, -ΝβΜalkyl) Cb4 alkane base. In another embodiment, with any of the specific embodiments described above and below, the invention has the following general structure:

或其任何醫藥可接受的鹽，其中： 99461.doc 2 21295670 R為獨立的部分飽和或不飽和的包含1、2、3或4個選自 N、〇與S的原子之8·、9-、10-或11_員雙環，其中該環的碳 原子係經0、1或2個氧基所取代，而該環係經0、1、2或3 個選自下列之取代基所取代：Cl 8烷基、CN4鹵烷基、鹵基、 氰基、硝基、-C(=0)Rb、-C(=0)〇Rb、-C(=0)NRaRa、-C(=NRa) NRaRa、_〇Ra 一〇c(=〇)Rb、ocpoww、〇c(=〇)N(Ra) S( = 0)2Rb、_〇C2 6 烷基 NRaRa …〇c2 6 烷基 〇Ra、_SRa、 ，S(=0)Rb、-S(=0)2Rb、-S(=〇)2NRaRa、-S(=0)2N(Ra)C(=0) Rb、-S(=0)2N(Ra)C(=0)0Rb、-S(=0)2N (Ra)C(=0)NRaRa、 -NRaRa、-N(Ra)C(=0)Rb、-N(Ra)C(=0)0Rb、-N(Ra)C(=〇) NRaRa、-N(Ra)C(=NRa)NRaRa、-N(Ra)S(=0)2Rb、-N(Ra)S(=〇)2 NRaRa、-NRaC2_6烧基 NRaRa與-NRaC2.6烷基 ORa ; R4為H或甲基； R為獨立的’在個別實例中，H或Rb ;而 Rb為獨立的，在個別實例中，苯基、芊基或烷基，該 苯基、苄基與(：1-6烷基係經〇、丨、2或3個選自下列之取代基 所取代：鹵基、cle4烷基、Cl 3鹵烷基、-〇Ci 4烷基、_丽2、 -NHCw烧基、-N(Ci-4燒基）Cle4烧基。 在另一個具體實施例中，加上任何一個上述與下述的具 體實施例，X為N而〆代表單鍵。 在另-個具體實施例中，加上任何—個上述與下述的具 體實施例，X為C而〆"代表雙鍵。 在另-個具體實施例中，加上任何__個上述與下述的具 體實施例，X為c而〆代表單鍵。 99461.doc -17. 1295670 在另一個具體實施例中，加上任何一個上述與下述的具 體實施例，R1為含有1、2、3或4個選自N、〇與8的原子之 飽和、部分飽和或不飽和的5_、6.或7_員環，其中該環的碳 原子係經0、丨或2個氧基所取代，而該環係經〇、丨、2或3 ^選自下列之取代基所取代：&烧基、&齒烷基、齒基、 氰基、硝基、-C(=0)Rb、-C(=〇)〇Rb、.c(=(^NRaRa、_c(=NRa)Or any pharmaceutically acceptable salt thereof, wherein: 99461.doc 2 21295670 R is an independently partially saturated or unsaturated group comprising 1, 2, 3 or 4 atoms selected from N, fluorene and S. a 10- or 11-membered bicyclic ring wherein the carbon atom of the ring is substituted with 0, 1 or 2 oxy groups, and the ring system is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of: Cl 8 alkyl, CN 4 haloalkyl, halo, cyano, nitro, -C(=0)Rb, -C(=0)〇Rb, -C(=0)NRaRa, -C(=NRa) NRaRa, _〇Ra a 〇c(=〇)Rb, ocpoww, 〇c(=〇)N(Ra) S(=0)2Rb, _〇C2 6 alkyl NRaRa ... 〇c2 6 alkyl 〇Ra, _SRa , S(=0)Rb, -S(=0)2Rb, -S(=〇)2NRaRa, -S(=0)2N(Ra)C(=0) Rb, -S(=0)2N( Ra)C(=0)0Rb, -S(=0)2N (Ra)C(=0)NRaRa, -NRaRa, -N(Ra)C(=0)Rb, -N(Ra)C(=0 ) 0Rb, -N(Ra)C(=〇) NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=0)2Rb, -N(Ra)S(=〇)2 NRaRa, -NRaC2_6 alkyl NRaRa and -NRaC2.6 alkyl ORa; R4 is H or methyl; R is independent 'in individual instances, H or Rb; and Rb is independent, in individual instances, phenyl , mercapto or alkyl, the phenyl, benzyl and (: 1-6 alkane The base is substituted with hydrazine, hydrazine, 2 or 3 substituents selected from the group consisting of halo, cle4 alkyl, Cl 3 haloalkyl, -〇Ci 4 alkyl, _Li 2, -NHCw alkyl, N (Ci-4 alkyl) Cle4 alkyl. In another embodiment, plus any one of the above and the following specific embodiments, X is N and 〆 represents a single bond. In another embodiment In addition to any of the specific embodiments described above and below, X is C and 〆" represents a double bond. In another embodiment, any of the above-described and specific embodiments are added, X is c and 〆 represents a single bond. 99461.doc -17. 1295670 In another embodiment, plus any one of the above and the following specific embodiments, R1 is 1, 2, 3 or 4 selected from a saturated, partially saturated or unsaturated 5-, 6. or 7-membered ring of N, fluorene and 8 wherein the ring carbon atom is substituted by 0, hydrazine or 2 oxy groups, and the ring is 〇, 丨, 2 or 3 ^ is substituted with a substituent selected from: & calcination, & dentyl, dentyl, cyano, nitro, -C(=0)Rb, -C(=〇 )〇Rb,.c(=(^NRaRa, _c(=NRa)

NRaRa > .〇Ra . .〇C( = 〇)Rb . .〇C( = 〇)NRaRa ^ .〇C( = 〇)N (Ra)S( = 〇)2Rb、-〇C2-6 烧基 NRaRa、〇C2 6烧基 〇Ra、_sRa、 -S(=〇)Rb . -S(=0)2Rb . -S(=0)2NRaRa . -S(=0)2N(Ra)C (=〇)Rb ^ -S(=0)2N(Ra)C(=〇)〇Rb , .S(=0)2N(Ra)C(=0) NR R、-NR R、-N(Ra)C(=〇)Rb、，N(Ra)c(=〇)〇Rb、 -N(Ra)C(=〇)NRaRa、_N(Ra)C(=NRa)NRaRa、_N(Ra)S(=0)2 R、-N(R)S(=0)2NRaRa、.NRaC2j*NRaRa 與 _NRaCw 烧 基 ORa 〇 在另一個具體實施例中，加上任何一個上述與下述的具 體實施例，R1為吡啶基、呋喃基、硫苯基或嘧啶基，其任 何一個係經0、1、2或3個選自Cw烷基、Ci4齒烷基與鹵基 之取代基所取代。 在另一個具體實施例中，加上任何一個上述與下述的具 體實施例，R1為吡啶基、呋喃基、硫苯基或嘧啶基，其任 何一個係經卜2或3個選自cy烷基、Ci4_烷基與鹵基之取 代基所取代。 在另一個具體實施例中，加上任何一個上述與下述的具 體實施例，R1為吡啶基、呋喃基、硫苯基或嘧啶基。 99461.doc -18- 1295670 在另一個具體實施例中，加上任何一個上述與下述的具 體實施例，R1為經卜2或3個選自下列之取代基所取代= 烷基、Cw鹵烷基、鹵基、氰基、硝基、_c(=C))Rb、_c(=〇)〇Rb、 -C(=〇)NRaRa、-C(=NRa)NRaRa、_0Ra、_〇c(=〇)Rb、_〇c(=〇) NRaRa、-〇C(=0)N(Ra)S(=0)2Rb、_OC2 6烷基NRaRa、 ^^2-6 烧基 ORa、-SRa、-S(=0)Rb、·8(=0)2Μ、-S(=〇)2NRaRa、 S(=0)2N(Ra)C(=0)Rb、-S(=0)2N(Ra)C(=0) 〇Rb、-S卜〇)2nNRaRa > .〇Ra . .〇C( = 〇)Rb . .〇C( = 〇)NRaRa ^ .〇C( = 〇)N (Ra)S( = 〇)2Rb, -〇C2-6 NRaRa, 〇C2 6 base 〇Ra, _sRa, -S(=〇)Rb . -S(=0)2Rb . -S(=0)2NRaRa . -S(=0)2N(Ra)C (=〇 Rb ^ -S(=0)2N(Ra)C(=〇)〇Rb , .S(=0)2N(Ra)C(=0) NR R, -NR R, -N(Ra)C( =〇)Rb,,N(Ra)c(=〇)〇Rb, -N(Ra)C(=〇)NRaRa, _N(Ra)C(=NRa)NRaRa, _N(Ra)S(=0) 2 R, -N(R)S(=0)2NRaRa, .NRaC2j*NRaRa and _NRaCw alkyl ORa 〇 In another embodiment, plus any one of the above and the following specific examples, R1 is pyridine Any of a group, a furyl group, a thiophenyl group or a pyrimidinyl group, which is substituted by 0, 1, 2 or 3 substituents selected from the group consisting of a Cw alkyl group, a Ci4 dentate group and a halogen group. In another embodiment, plus any one of the above and the following specific examples, R1 is pyridinyl, furyl, thiophenyl or pyrimidinyl, any one of which is 2 or 3 selected from cynes Substituted by a substituent of a Ci4_alkyl group and a halogen group. In another embodiment, plus any one of the above specific examples, R1 is pyridinyl, furyl, thiophenyl or pyrimidinyl. 99461.doc -18- 1295670 In another embodiment, plus any one of the above and the following specific examples, R1 is substituted with 2 or 3 substituents selected from the group consisting of: alkyl, Cw halogen Alkyl, halo, cyano, nitro, _c(=C))Rb, _c(=〇)〇Rb, -C(=〇)NRaRa, -C(=NRa)NRaRa, _0Ra, _〇c( =〇)Rb, _〇c(=〇) NRaRa, -〇C(=0)N(Ra)S(=0)2Rb, _OC2 6 alkyl NRaRa, ^^2-6 alkyl ORa, -SRa, -S(=0)Rb,·8(=0)2Μ, -S(=〇)2NRaRa, S(=0)2N(Ra)C(=0)Rb, -S(=0)2N(Ra) C(=0) 〇Rb, -S 〇) 2n

(Ra)C(=0)NRaRa、-NRaRa、-N(Ra)c(=〇)Rb、_N(Ra)c(二） 〇Rb > -N(Ra)C(=0)NRaRa ^ -N(Ra)C(=NRa)NRaRa > -N(Ra)S (=0)2Rb、-N(Ra)S(=〇)2NRaRa、-NRaC2-6 烷基 NRaRa 與 -NRaC2.6烷基 〇Ra。 在另一個具體實施例中，加上任何一個上述與下述的具 體實施例，R1為經卜2或3個選自Cw烷基、Cw鹵烷基、鹵 基與-0Ra的取代基所取代之苯基。 在另一個具體實施例中，加上任何一個上述與下述的具 .體實施例，R2是獨立的含有i、2、3或4個選自N、〇與8的 原子之部分飽和或不飽和的8-、、1〇_或U-員雙環，其中 該環的碳原子，係經〇、1或2個氧基所取代，而該環係經Q、 1、2或3個選自下列之取代基所取代：Gy烷基、Ci4鹵烷基、 鹵基、氰基、硝基、-C(=〇)Rb、_cC=0)0Rb、_C(=C〇NilaIla、 -C(~NR )NR Ra - .〇Ra x -〇C(=0)Rb - -0C(=0)NRaRa . -〇C(=0)N(Ra)S(=0)2Rb、_〇C2 6 烷基 NRaRa、_〇C2 6 烷基 OR、-SRa、-S(=〇)Rb、-S(=〇)2Rb、-S(=〇)2NRaRa、 -S(=0)2N(Ra)C(=0)Rb . -S(=0)2N(Ra)C(=0)0Rb > -S(=〇)2n 99461.doc •19- 1295670 (Ra)C(=0)NRaRa、-NRaRa、-N(Ra)C(=0)Rb、-N(Ra)C(=0) ORb、_N(Ra)C(=0)NRaRa、-N(Ra)C(=NRa)NRaRa、-N(Ra)S (=0)2Rb、-N(Ra)S(=0)2NRaRa、-NRaC2-6 烧基 NRaRa 與 -NRaC2-6烷基 ORa。 在另一個具體實施例中，加上任何一個上述與下述的具 體實施例，R2為喹啉-8-基，苯并咩唑-4-基、苯并噻唑-4-基或喹吟啉-5-基，其中一個係經0、1、2或3個選自下列之 取代基所取代：烷基、Cm鹵烷基、_基、氰基、硝基、 -C(=0)Rb、_C(=0)0Rb、-C(=0)NRaRa、-C(=NRa)NRaRa、 -ORa、-0C(=0)Rb、-0C(=0)NRaRa、-0C(=0)N(Ra)S(=0)2Rb、 -〇C2_6 烷基 NRaRa、-0(：2.6烷基01^、-SRa、-S(=0)Rb、 -S(=0)2Rb、-S(=0)2NRaRa、-S(=0)2N(Ra)C(=0)Rb、-S(=0)2N (Ra)C(=0)0Rb、_S(=0)2N(Ra)C(=0)NRaRa、-NRaRa、 -N(Ra)C(=0)Rb、-N(Ra)C(=0)0Rb、-N(Ra)C(=0)NRaRa、 -N(Ra)C(=NRa)NRaRa、-N(Ra)S(=0)2Rb、-N(Ra)S(=0)2 NRaRa、-NRaC2.6烷基 NRaRa與-NRaC2.6烷基 ORa。 在另一個具體實施例中，加上任何一個上述與下述的具 體實施例，R3為Η。 在另一個具體實施例中，加上任何一個上述與下述的具 體實施例，RY為甲基。 在另一個具體實施例中，加上任何一個上述與下述的具 體實施例，R3與R3'合併它們所附接的碳原子形成環丙基。 在另一個具體實施例中，加上任何一個上述與下述的具 體實施例，R4為Η。 99461.doc -20- 1295670 在另一個具體實施例中，加上任何一個上述與下述的具 體實施例，R4為甲基。 ’、 本發明另一方面係有關治療下列疾病的方法··急性、發 炎性與神經病變性疼痛、牙痛、一般性頭痛、偏頭痛、聚 叢性頭痛、混合性血管與非血管症候群、緊張性頭痛、一 般性發炎、關節炎、風濕病、骨關節炎、發炎性腸疾 '焦 慮、憂鬱症、發炎性眼疾、發炎性或不穩定性膀胱病症、 牛皮癬、發炎性成分引起的皮膚不適、慢性發炎性病情、 發炎性疼痛與相關的痛覺過敏與異常疼痛、神經病變性疼 痛與相關的痛覺過敏與異常疼痛、糖尿病神經病變性疼 痛、灼熱痛、交感神經所致的疼痛、去傳入神經症候群、 氣喘、上皮細胞組織損害或功能障礙、單純泡疹，呼吸道、 泌尿生殖系統、胃腸或血管區域的臟器蠕動失調，傷口' 灼傷、過敏性皮膚反應、搔疼症、白斑病、—般性胃腸病 症、月潰瘍、十二指腸潰瘍、腹瀉、致壞死劑造成的胃損 傷、頭髮生長、血管運動或過敏性鼻炎、支氣管病症或膀 胱病症，包括根據任何一個上述的具體實施例施用化合物。 本發明另一方面係有關醫藥組合物，包括根據任何一個 上述的具體實％例之化合#勿，以丨醫藥可接受的稀釋劑或 載體。 本發明另一方面係有關根據任何一個上述的具體實施例 之化合物做為藥物之用途。 月另方面係有關根據任何一個上述的具體實施例 之化口物的用途’其係在製造治療下列疾病的藥物··急性、 99461.doc 1295670 發炎性與神經病變性疼痛、牙痛、一般性頭痛、偏頭痛、 聚叢性頭痛、混合性企管與非血管症候群、緊張性頭痛、 一般性發炎、關節炎、風濕病、骨關節炎、發炎性腸疾' 焦慮、憂鬱症、發炎性眼疾、發炎性或不穩定性膀胱病症、 牛皮癬、發炎性成分引起的皮膚不適、慢性發炎性病情、 發炎性疼痛與相關的痛覺過敏與異常疼痛、神經病變性疼 痛與相關的痛覺過敏與異常疼痛、糖尿病神經病變性疼 痛、灼熱痛、父感神經所致的疼痛、去傳入神經症候群、 氣喘、上皮細胞組織損害或功能障礙、單純泡疹，呼吸道、 泌尿生殖系統、胃腸或企管區域的臟器罐動失調，傷口、 灼傷、過敏性皮膚反應、搔癢症、白斑病、一般性胃腸病 症、胃潰瘍、十二指腸潰瘍、腹瀉、致壞死劑造成的胃損 傷、頭髮生長、灰管運動或過敏性鼻炎、支氣管病症或膀 胱病症。 本發明化合物通常可能具有數個不對稱中心，而且典型 地晝成消旋混合物形式。本發明也要包括消旋混合物、部 分的消旋混合物與個別的對掌體與非鏡象異構物。 除非特別說明，否則下列定義適用於專利說明書與請求 項中所見的術語： 烧基”意指包括最少α個最多冷個碳原子之支鏈、環 狀或直鏈或任何這三個的組合之烧基，其中a與沒代表整 數。在這個部分中所說明的烷基可能也包含1或2個雙或三 鍵。Cw烧基的實例包括但不限於下列者： 99461.doc(Ra)C(=0)NRaRa, -NRaRa, -N(Ra)c(=〇)Rb, _N(Ra)c(b) 〇Rb > -N(Ra)C(=0)NRaRa ^ - N(Ra)C(=NRa)NRaRa > -N(Ra)S (=0)2Rb, -N(Ra)S(=〇)2NRaRa, -NRaC2-6 alkyl NRaRa and -NRaC2.6 alkyl 〇Ra. In another embodiment, plus any one of the above and the following specific examples, R1 is substituted with 2 or 3 substituents selected from the group consisting of Cw alkyl, Cw haloalkyl, halo and -0Ra. Phenyl. In another embodiment, plus any one of the above and below embodiments, R2 is independently saturated or not containing i, 2, 3 or 4 atoms selected from N, 〇 and 8. a saturated 8-, 1 〇 or U-membered bicyclic ring wherein the ring carbon atom is substituted with hydrazine, 1 or 2 oxy groups, and the ring system is selected from Q, 1, 2 or 3 Substituted by the following substituents: Gy alkyl, Ci4 haloalkyl, halo, cyano, nitro, -C(=〇)Rb, _cC=0)0Rb, _C(=C〇NilaIla, -C(~ NR )NR Ra - .〇Ra x -〇C(=0)Rb - -0C(=0)NRaRa . -〇C(=0)N(Ra)S(=0)2Rb, _〇C2 6 alkyl NRaRa, _〇C2 6 alkyl OR, -SRa, -S(=〇)Rb, -S(=〇)2Rb, -S(=〇)2NRaRa, -S(=0)2N(Ra)C(= 0) Rb . -S(=0)2N(Ra)C(=0)0Rb > -S(=〇)2n 99461.doc •19- 1295670 (Ra)C(=0)NRaRa, -NRaRa, - N(Ra)C(=0)Rb, -N(Ra)C(=0) ORb, _N(Ra)C(=0)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra S(=0)2Rb, -N(Ra)S(=0)2NRaRa, -NRaC2-6 alkyl group NRaRa and -NRaC2-6 alkyl ORa. In another embodiment, plus any of the above In the specific embodiment described below, R 2 is a quinoline-8-yl group, And oxazol-4-yl, benzothiazol-4-yl or quinoxalin-5-yl, one of which is substituted by 0, 1, 2 or 3 substituents selected from the group consisting of alkyl, Cm halide Alkyl group, _ group, cyano group, nitro group, -C(=0)Rb, _C(=0)0Rb, -C(=0)NRaRa, -C(=NRa)NRaRa, -ORa, -0C(= 0) Rb, -0C(=0)NRaRa, -0C(=0)N(Ra)S(=0)2Rb, -〇C2_6 alkyl NRaRa, -0 (: 2.6 alkyl 01^, -SRa, - S(=0)Rb, -S(=0)2Rb, -S(=0)2NRaRa, -S(=0)2N(Ra)C(=0)Rb, -S(=0)2N (Ra) C(=0)0Rb, _S(=0)2N(Ra)C(=0)NRaRa, -NRaRa, -N(Ra)C(=0)Rb, -N(Ra)C(=0)0Rb, -N(Ra)C(=0)NRaRa, -N(Ra)C(=NRa)NRaRa, -N(Ra)S(=0)2Rb, -N(Ra)S(=0)2 NRaRa,- NRaC2.6 alkyl NRaRa with -NRaC2.6 alkyl ORa. In another embodiment, plus any of the specific embodiments described above and below, R3 is Η. In another embodiment, plus any of the specific embodiments described above and below, RY is a methyl group. In another embodiment, plus any one of the above and the following specific examples, R3 and R3' combine with the carbon atom to which they are attached to form a cyclopropyl group. In another embodiment, plus any of the specific embodiments described above and below, R4 is Η. 99461.doc -20- 1295670 In another embodiment, plus any one of the above specific examples, R4 is a methyl group. ', another aspect of the present invention relates to the treatment of the following diseases: acute, inflammatory and neuropathic pain, toothache, general headache, migraine, cluster headache, mixed vascular and non-vascular syndrome, tension headache , general inflammation, arthritis, rheumatism, osteoarthritis, inflammatory bowel disease 'anxiety, depression, inflammatory eye disease, inflammatory or unstable bladder disease, psoriasis, skin irritation caused by inflammatory ingredients, chronic inflammation Sexually transmitted diseases, inflammatory pain and related hyperalgesia and abnormal pain, neuropathic pain and related hyperalgesia and abnormal pain, diabetic neuropathic pain, burning pain, sympathetic pain, afferent neurosis, asthma, Epithelial cell tissue damage or dysfunction, simple herpes, respiratory tract, genitourinary system, gastrointestinal or vascular area, organ peristalsis, wound 'burn, allergic skin reaction, ache, white spot disease, general gastrointestinal disease, Moon ulcer, duodenal ulcer, diarrhea, stomach damage caused by necrosis agent, head Growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders, comprising administering a compound according to any of the embodiment described above a specific. Another aspect of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable diluent or carrier according to any of the above specific examples. Another aspect of the invention relates to the use of a compound according to any one of the above specific embodiments as a medicament. The other aspect relates to the use of a mouthpiece according to any of the above specific embodiments, which is for the manufacture of a medicament for the treatment of the following diseases: Acute, 99461.doc 1295670 Inflammatory and neuropathic pain, toothache, general headache, Migraine, cluster headache, mixed management and non-vascular syndrome, tension headache, general inflammation, arthritis, rheumatism, osteoarthritis, inflammatory bowel disease ' anxiety, depression, inflammatory eye disease, inflammatory Or unstable bladder disorders, psoriasis, skin irritation caused by inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and abnormal pain, neuropathic pain and associated hyperalgesia and abnormal pain, diabetic neuropathic pain , burning pain, pain caused by paternal nerves, afferent neurosis, asthma, epithelial tissue damage or dysfunction, simple herpes, respiratory tract, genitourinary system, gastrointestinal or vascular organ dysfunction, wound , burns, allergic skin reactions, pruritus, leukoplakia, general gastroenterology , Gastric ulcer, duodenal ulcers, diarrhea, necrotizing agents cause gastric damage, hair growth, motion pipe ash or allergic rhinitis, bronchial disorders or bladder disorders. The compounds of the invention may generally have several asymmetric centers and are typically in the form of a racemic mixture. The invention also includes racemic mixtures, partial racemic mixtures and individual pairs of palm and non-image isomers. Unless otherwise stated, the following definitions apply to the terms used in the patent specification and claims: "alkyl" means a branch, a ring or a straight chain or a combination of any three comprising at least a few of the most cold carbon atoms. An alkyl group, wherein a and not represent an integer. The alkyl group illustrated in this section may also contain 1 or 2 double or triple bonds. Examples of Cw alkyl groups include, but are not limited to, the following: 99461.doc

(S -22- 1295670 π苯并基’’單獨或合併時，意指二價基團C4H4=，其一個代 表為-CH=CH-CH=CH-，因此當相鄰地附接於另一個環時形 成類苯環，例如四氫萘、吲哚與類似者。 ”氧基π與"硫基π之術語分別代表=〇(比如在羰基中者）與 (比如在硫羰基中者）基。 基”或”鹵素’’意指選自F、Cl、Br與I的鹵原子。 ’’Cv-W鹵烷基”意指如上述之烷基，其中任何數目―至少為 1一的附著於烷基鏈的氫原子係經F、c卜汾或1所取代。 雜％意指包括至少丨個碳原子與至少丨個選自N、〇與s 的其他原子之環。 在請求項中可以發現的雜 兄的雜ί衣的實例包括但不限於下列(S -22- 1295670 π-benzo-', when taken alone or combined, means that the divalent group C4H4=, one of which is represented by -CH=CH-CH=CH-, thus when attached adjacently to another The ring forms a benzene-like ring, such as tetrahydronaphthalene, anthracene and the like. The terms "oxy π and " thio π represent = 〇 (such as in a carbonyl group) and (such as in a thiocarbonyl group). The term " or "halogen" means a halogen atom selected from the group consisting of F, Cl, Br and I. ''Cv-W haloalkyl" means an alkyl group as defined above, wherein any number is at least one. The hydrogen atom attached to the alkyl chain is substituted by F, c or dip. 1. Hetero% means a ring comprising at least one carbon atom and at least one other atom selected from N, 〇 and s. Examples of miscellaneous clothes that can be found in the miscellaneous include, but are not limited to, the following

99461.doc99461.doc

12956701295670

了仵的虱原子"係指那些做為 鍵遠接l . 勹雅％的一部份並藉兩個身 鍵連接(例如六氫吡啶），而允 ΓΗ , 1U外σ卩的鍵可以被例如I 或CH3所取代的氮原子。 ”醫藥可接受的鹽”意指藉慣用方 朴滅土 4 I 兵衣W 而且為熟諳说The 虱 虱 虱 & & 系 系 系 系 系 系 系 系 系 系 & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & & For example, a nitrogen atom substituted by I or CH3. "Pharmaceutically acceptable salt" means to use the ordinary to destroy the soil 4 I soldier clothes W and to be familiar with

1者熟知的藥理上可接受的鹽”包括無機和有機酸 的驗性鹽，包括但不限於氫氣酸、氫漠酸、硫酸、構酸、 :烧績酸、乙料酸、蘋果酸、乙酸、草酸、酒石酸、揭 才豕駄、礼酸、反丁烯二酸、琥珀酸、順丁烯二酸、柳酸、 爷酸、苯基乙酸、杏仁酸與類似者。t本發明的化合物包 括諸如羧基的酸官能基時，則該羧基的適當醫藥可接受陽 離子對是熟諳此技藝者所熟知的，而且包括鹼金屬、鹼土 金屬、銨、四級銨陽離子與類似者。”有關藥理可接受的鹽，, 的另外實例請參照下文與Berge等J. Pharm Sci 66:1 (1977) 〇 99461.doc -24- 1295670 π飽和或不飽和”包括經由氫飽和的取代基，經由氫完全 不飽和的取代基以及經由氫部分飽和的取代基。 ”離去基’’ 一般表示很容易被親核基，諸如胺、硫醇或醇 類親核基取代的基。此類離去基是此技藝所熟知。此類離 去基的實例包括但不限於Ν_羥基琥珀醯亞胺、义羥基苯並 三唾、鹵化物、三氟甲烷磺酸、甲苯磺酸與類似物。較佳 的離去基’只要是適合都會在本文中表示。 保護基"通常表示用來保護選取的反應基之此技藝所熟 知的基，諸如羧基、胺基、羥基、巯基與類似者，以免進 行諸如親核基、親電基、氧化、還原與類似者之前述的不 必要反應。較佳的保護基，只要是適合都會在本文表示。 胺基保護基的實例包括，但不限於芳烷基、經取代的芳烷 基、環烯烷基與經取代的環烯烷基、烯丙基、經取代的烯 丙基、醯基、烷氧羰基 '芳烷氧羰基、矽烷基與類似者。 芳烷基的實例包括，但不限於苄基、鄰甲芊基、三苯甲基 〃 一本甲基’其可視情形經鹵素、烧基、烧氧基、經基、 硝基、醯基胺基、醯基與類似者，以及諸如鱗酸鹽與銨鹽 之鹽類所取代。芳基的實例包括苯基、萘基、茚基、蒽基、 9-(9-苯第基）、菲基、莊基與類似物。環烯烷基或經取代的 環烯烷基之實例較佳者是具有6-10個碳原子，包括但不限 於％己稀甲基與類似者。適當的醯基、烷氧羰基與芳烷氧 敢基包括爷氧幾基、三級丁氧M基、$丁氧魏基、爷醯基、 經取代的苄醯基、丁醯基、乙醯基、1氟乙醯基、三氯乙 醯基、鄰苯二甲醯基與類似物。保護基的混合物可用來保 99461.doc -25- !295670 護相同的胺基，諸如初級胺基可藉芳烷基與芳烷氧羰基來 保護。胺基保護基亦可與它們所附接的氮形成雜環，例如 12-雙（亞甲基）苯、鄰苯二甲醯亞胺基、琥珀醯亞胺基、順 丁烯二醯亞胺基與類似物；而且，這些雜環基可進一步包 括鄰接的芳基與環烷環。此外，該雜環基可以為單-、二_ 或三-取代，諸如硝基鄰苯二甲醯亞胺基。也可經由形成諸 如鹽酸鹽、甲苯績酸、三氟乙酸與類似物之加成鹽，保護 胺基免於諸如氧化之不必要的反應。很多的胺基保護基也 適合保護羧基、羥基與巯基。例如芳烷基。烷基也是適合 保護羥基與硫基的基，諸如三級丁基。 石夕烧基保護基為視情形經一或多個烷基、芳基與芳烷基 取代之石夕原子。適當的矽院基保護基，包括但不限於三甲 基石夕烧基、三乙基矽烷基、三異丙基矽烷基、三級丁基二 甲基石夕烧基、二甲基苯基矽烷基、12—雙（二甲基矽烷基） 苯、1，2-雙（二甲基矽烷基）乙烷與二苯基甲基矽烷基。胺基 的矽烷化提供單或雙矽烷胺基。胺基醇化合物的矽烷化會 產生Ν，Ν，〇·三矽烷基衍生物。藉由例如金屬氫氧化物或氟 化銨試劑，做為不連續的反應步驟，或是與醇基的反應期 間在原位進行處理，可以很方便地完成將矽烷基官能基由 矽烷基醚官能基去除。適當的矽烷化劑為例如三甲基矽烷 基氣化物、三級丁基-二甲基矽烷基氣化物、苯基二甲基矽 烷基氣化物、二苯基甲基矽烷基氣化物，或是其與咪唑或 DMF的合併產物。胺基之矽烷化與矽烷基保護基的去除方 法，是熟諳此技藝者所熟知。由對應的胺基酸、胺基酸醯 99461.doc -26- 1295670 胺或胺基酸酯製備這些胺衍生物 酸/脸苴缺匕上 万法疋熟諳包括胺基 w胺基酸8旨或胺基醇化學的有機化學技藝者所孰知。 去除保護基是在不會影響該分子的剩餘部分之條件下進 行。這些方法是此技藝所熟知，並包括酸水解、氯解斑類 :者。較佳的方法涉及去除保護基，諸如藉由利用溶於諸 乙酵、乙酸與類似者或其混合物之適當溶劑系統的pd/c 進行氫解^料㈣基。三級丁氧絲保護基可以利用 諸如HC1或三氟乙酸之無機或有機酸，於諸如二吟烧或二氣 甲院之適纽劑系統巾加以絲4成的胺基鹽可以很方 便的進行中和而產生自由態胺。諸如甲基、乙基、节基、 三級丁基、4·甲氧苯基甲基與類似者之叛基保護基，可以 利用熟諳此技藝者熟知之水解與氫解條件來去除。 我們應該了解，本發明的化合物可能包含存在互變異構 物形式的基，諸如環狀與非環狀甲瞇與胍基、雜原子取代 的雜芳基（Y’ = 0、s、NR)與類似者，其係以不列實例說明··A well-known pharmacologically acceptable salt" includes inorganic salts of organic and organic acids, including but not limited to hydrogen acid, hydrogen acid, sulfuric acid, acid, calcined acid, acetic acid, malic acid, acetic acid. , oxalic acid, tartaric acid, sputum, succinic acid, fumaric acid, succinic acid, maleic acid, salicylic acid, yoghurt, phenylacetic acid, mandelic acid and the like. t The compounds of the invention include Suitable acid-acceptable cationic pairs of such carboxyl groups, such as the acid functional groups of the carboxyl group, are well known to those skilled in the art and include alkali metal, alkaline earth metal, ammonium, quaternary ammonium cations and the like. For additional examples of salts, please refer to the following Berge et al. J. Pharm Sci 66:1 (1977) 〇99461.doc -24-1295670 π saturated or unsaturated" including substituents via hydrogen saturation, completely unsaturated via hydrogen Substituents and substituents which are partially saturated via hydrogen. "Leaving group" generally means a group which is readily substituted by a nucleophilic group such as an amine, thiol or alcohol nucleophilic group. Such leaving groups are well known in the art. Examples of such leaving groups include, but are not limited to, hydrazine-hydroxysuccinimide, hydroxybenzotris, halides, trifluoromethanesulfonic acid, toluenesulfonic acid, and the like. Preferred leaving groups will be indicated herein as long as they are suitable. Protecting groups " generally denote groups well known in the art for protecting selected reactive groups, such as carboxyl groups, amine groups, hydroxyl groups, sulfhydryl groups and the like, to avoid such as nucleophilic groups, electrophilic groups, oxidation, reduction and the like. The aforementioned unnecessary reaction. Preferred protecting groups are indicated herein as appropriate. Examples of amine protecting groups include, but are not limited to, aralkyl, substituted aralkyl, cycloalkenyl and substituted cycloalkyl, allyl, substituted allyl, decyl, alkane Oxycarbonyl 'aralkyloxycarbonyl, decyl and the like. Examples of aralkyl groups include, but are not limited to, benzyl, o-mercapto, trityl hydrazine, a methyl group, which may optionally be halogen, alkyl, alkoxy, thio, nitro, decylamine. Substituents, sulfhydryl groups and the like, as well as salts such as sulphates and ammonium salts. Examples of the aryl group include a phenyl group, a naphthyl group, an anthracenyl group, a fluorenyl group, a 9-(9-phenyldiyl group), a phenanthryl group, a succinyl group, and the like. Examples of cycloalkylene or substituted cycloalkenyl groups preferably have from 6 to 10 carbon atoms, including but not limited to % hexamethylene and the like. Suitable fluorenyl, alkoxycarbonyl and aralalkyloxy groups include anthraceneoxy, tertiary butoxy M, butyloxycarbyl, fluorenyl, substituted benzinyl, butyl fluorenyl, ethyl fluorenyl, 1 Fluorinyl, trichloroethylene, phthalic acid and the like. A mixture of protecting groups can be used to protect the same amine group, such as a primary amine group, which can be protected by an aralkyl group and an aralkoxycarbonyl group. Amino protecting groups may also form heterocycles with the nitrogen to which they are attached, such as 12-bis(methylene)benzene, phthalimido, amber succinimide, maleimide Bases and analogs; moreover, these heterocyclic groups may further comprise contiguous aryl and cycloalkane rings. Further, the heterocyclic group may be a mono-, di- or tri-substituted group such as a nitrophthalimido group. It is also possible to protect the amine group from unnecessary reactions such as oxidation by forming an addition salt such as hydrochloride, toluic acid, trifluoroacetic acid and the like. Many amine protecting groups are also suitable for protecting carboxyl groups, hydroxyl groups and sulfhydryl groups. For example aralkyl. The alkyl group is also a group suitable for protecting a hydroxyl group and a sulfur group, such as a tertiary butyl group. The sulphate protecting group is a stellite atom substituted by one or more alkyl, aryl and aralkyl groups as the case may be. Suitable broth-based protecting groups, including but not limited to trimethyl sulfonium, triethyl decyl, triisopropyl decyl, tert-butyl dimethyl oxalate, dimethyl phenyl decyl 12-bis(dimethylalkylalkyl)benzene, 1,2-bis(dimethylalkylalkyl)ethane and diphenylmethyldecylalkyl. The decanolation of an amine group provides a mono or didecylamine group. The decanolation of an amino alcohol compound produces a ruthenium, osmium, osmium tridecyl derivative. It is convenient to carry out the conversion of the alkylidene functional group from the alkyl ether ether by, for example, a metal hydroxide or ammonium fluoride reagent, as a discontinuous reaction step, or in situ during the reaction with an alcohol group. Base removal. Suitable decylating agents are, for example, trimethyl decyl alkyl hydride, tertiary butyl dimethyl decyl vapor, phenyl dimethyl decyl vapor, diphenylmethyl decyl vapor, or Its combined product with imidazole or DMF. Methods for the removal of amine decyl and decyl protecting groups are well known to those skilled in the art. Preparation of these amine derivatives by the corresponding amino acids, guanidinium amide 99461.doc -26-1295670 amines or amino acid esters, acid/face defects, hydroxy formulas including amino-w-amino acids or Amino acid chemistry is known to those skilled in the art of organic chemistry. Removal of the protecting group is carried out without affecting the remainder of the molecule. These methods are well known in the art and include acid hydrolysis, chlorolysis; A preferred method involves the removal of a protecting group, such as by hydrogenolysis of the (d) group using pd/c dissolved in a suitable solvent system of ethyl lactate, acetic acid and the like or mixtures thereof. The tertiary-stage butadiene-protecting group can utilize an inorganic or organic acid such as HCl or trifluoroacetic acid, and can be conveniently carried out in an amine-based salt such as a bismuth or a gas-filled system. Neutralization produces free amines. Rebel protecting groups such as methyl, ethyl, benzyl, tributyl, 4-methoxyphenylmethyl and the like can be removed by hydrolysis and hydrogenolysis conditions well known to those skilled in the art. It should be understood that the compounds of the invention may contain groups in the form of tautomeric forms, such as cyclic and acyclic formazan and fluorenyl, heteroatom-substituted heteroaryls (Y' = 0, s, NR) and Similarly, it is not listed as an example.

NHR· RHN^^NR" 1^1 RHN^^NHR" RN^^NHR"NHR· RHN^^NR" 1^1 RHN^^NHR"RN^^NHR"

NR· # & NHR，NR· # & NHR,

RR

99461.doc 1295670 儘官在本文中將其中一個型式命名、說明、展示與/或請求 專利，但是這此類名稱、說明、展示與/或請求專利都想要 自然地包括所有的互變異構物型式。 本發明化合物的前藥亦為本發明所涵蓋。前藥是一種活 性或非活性化合物，其會經由諸如水解、代謝反應與類似 者之活體内的生理作用而化學修飾，使得前藥施用於病患 後旎夠成為本發明的化合物。前藥之製造與使用所涉及的 適當性與技術是熟諳此技藝者所熟知的，有關涉及酯類的 前藥之一般性討論請參照Svensson與Tunek，Drug Metabolism Reviews 165(1988)以及 Bundgaard 以“糾 〇f Prodmgs，Elsevier(1985)。經過遮蔽的羧酸鹽陰離子的實例 包括各種酯類，諸如烷基（例如，甲基、乙基）、環烷基（例 如，環己基）、芳烷基（例如，芊基、對·甲氧苄基）與烷氧羰 烷氧基（例如，新戊醯基氧基甲基）。胺基是經遮蔽成芳基羰 氧甲基取代的衍生物，其在活體内會被酯酶切斷而釋出自 由恶藥物與甲醛（Bungaard J. Med· Chem· 2503(1989))。而 且，含有酸性NH基的藥物諸如咪唑、亞醯胺、吲哚與類似 者都利用N-醯氧甲基加以遮蔽（Bundgaard Design 〇f99461.doc 1295670 In this document, one of the types is named, illustrated, displayed, and/or patented, but such names, descriptions, displays, and/or patents are intended to naturally include all tautomers. Type. Prodrugs of the compounds of the invention are also encompassed by the invention. A prodrug is an active or inactive compound that is chemically modified via physiological actions such as hydrolysis, metabolic reactions, and the like in vivo, such that the prodrug is administered to a patient and becomes a compound of the present invention. The appropriateness and techniques involved in the manufacture and use of prodrugs are well known to those skilled in the art. For a general discussion of prodrugs involving esters, please refer to Svensson and Tunek, Drug Metabolism Reviews 165 (1988) and Bundgaard. Correction f Prodmgs, Elsevier (1985). Examples of masked carboxylate anions include various esters such as alkyl (eg, methyl, ethyl), cycloalkyl (eg, cyclohexyl), aralkyl (for example, anthracenyl, p-methoxybenzyl) and alkoxycarbonylalkoxy (for example, neopentyloxymethyl). The amine group is a derivative which is blocked by an arylcarbonyloxymethyl group. It is cleaved by esterase in vivo to release free toxic drugs and formaldehyde (Bungaard J. Med Chem 2.53 (1989)). Moreover, drugs containing acidic NH groups such as imidazole, imipenem, anthracene and Similar uses are masked with N-methoxymethyl (Bundgaard Design 〇f

Prodrugs，Elsevier(1985))。羥基經遮蔽成酯類與醚類。Ep 039’051 (Sloan and Little，4/11/81)揭示 Mannich-驗異經肪酸 前藥，它們的製法與用途。 專利說明書與請求項包含利用”選自…與…"與"為... 或…”之語言的物種表列（有時稱為Markush*)。當在本申請 中使用這些語言時，除非特別說明，否則我們要整體的包 99461.doc •28- 1295670 括這個基或其任何單一的成員，或其任何次基團。使用這 個語言僅為了簡單表示之目的，無論如何也不會對需要去 除的個別原素或次基團做限制。 實驗 除非特別說明，否則所有材料都是市售者，而且不經進 一步純化直接使用。所有的等分都是表示重量，至於溫度， 除非另有說明，否則即是攝氏溫度。所有的微波爐輔助反 應都是利用瑞典Uppsala的Personal Chemistry製造之Smith > Synthesizer進行。所有的成分都顯示與其指定結構一致的 NMR光譜。熔點係採用Buchi裝置測定，而且未經訂正。質 譜資料係採用電喷霧離子化技術決定。正如藉由高效液相 色析（HPLC)所決定者，所有實例的純度都純化至> 90%。 Chiral HPLC係利用購自 Advanced Separation Technologies Inc.之Chirobiotic TAG管柱進行。除非特別說明，否則反 應係在室溫進行。 本文所用的縮寫如下： DMSO- 二甲礙 DMF- N，N-二曱基甲醯胺 THF- 四氫呋喃 Et20- 乙醚 EtOAc- 乙酸乙酯 MeOH- 甲醇 EtOH- 乙醇 MeCN- 乙腈 99461.doc -29- 1295670Prodrugs, Elsevier (1985)). The hydroxyl groups are masked into esters and ethers. Ep 039’051 (Sloan and Little, 4/11/81) reveals Mannich-tested fatty acid prodrugs, their preparation and use. The patent specification and claims contain a list of species (sometimes referred to as Markush*) using the language "selected from...and..." and "for... or...". When these languages are used in this application, we will include the entire package 99461.doc •28-1295670, including the base or any of its individual members, or any of its subgroups, unless otherwise stated. The use of this language is for the sole purpose of representation, and in no case limits the individual elements or subgroups that need to be removed. Experimental Unless otherwise stated, all materials were commercially available and used without further purification. All aliquots are weight, as for temperature, unless otherwise stated, it is Celsius. All microwave oven auxiliary reactions were performed using Smith > Synthesizer, manufactured by Personal Chemistry, Uppsala, Sweden. All components showed an NMR spectrum consistent with their assigned structure. Melting points were determined using a Buchi apparatus and were not corrected. The mass spectral data is determined by electrospray ionization. The purity of all the examples was purified to > 90% as determined by high performance liquid chromatography (HPLC). The Chiral HPLC system was carried out using a Chirobiotic TAG column available from Advanced Separation Technologies Inc. Unless otherwise stated, the reaction is carried out at room temperature. The abbreviations used herein are as follows: DMSO- dimethyl hydride DMF-N,N-dimercaptocaramine THF-tetrahydrofuran Et20-ethyl ether EtOAc-ethyl acetate MeOH-methanol EtOAc (EtOAc)

Mel- NMP- DCM- TFA- MP-carbonate- sat·· h- min-實例] 碘化甲烷 1 -曱基-2 -ϋ比1^ 闕 二氣曱烷 三氟乙酸 巨孔聚苯乙烯陰離子交換樹 脂，其為碳酸四曱基銨酯的樹 脂結合同等物 飽和 小時 分鐘Mel- NMP- DCM- TFA- MP-carbonate- sat·· h- min-example] Methyl iodide 1-mercapto-2-pyrene-pyrene 1^ 阙dioxane trifluoroacetic acid macroporous polystyrene anion exchange Resin, which is a resin of tetradecyl ammonium carbonate, which is equivalent to saturation for an hour.

(a)4-(6_氣基-嘧啶-4-基氧基）-苯并噻唑-2-基胺 將碳酸鉀（4.1 g，30 mmol，Aldrich)與二甲颯（10 ml)加入 100-mL 之含有 4,6-二氣基·嘴咬（9.0 g，60 mmol，Aldrich) 與2-胺基-苯并嗟嗤-4-醇（5.0 g，30 mmol，CarboGen)的圓 底燒瓶中。令反應混合物於95°C攪拌加熱4.5h，然後在室 溫下16h。過濾收集生成之固體，以水（500 mL)與二氣甲烷 (500 mL)洗並真空乾燥，取得黃色固體之標題化合物。 9946i.doc -30- 1295670 NHAc (b)N-[4-(6-氣基-嘧啶-4-基氧基）-苯并噻唑-2-基】-乙醯胺 令4-(6-氣基-嘧啶-4-基氧基）-苯并噻唑-2-基胺、實例 1(a)、（4.0 g，14 mmol)、甲苯（10 ml)與乙酸肝（4.1 mL，43(a) 4-(6-Gas-pyrimidin-4-yloxy)-benzothiazol-2-ylamine Addition of potassium carbonate (4.1 g, 30 mmol, Aldrich) and dimethylhydrazine (10 ml) to 100 -mL round bottom flask containing 4,6-diyl group, mouth bite (9.0 g, 60 mmol, Aldrich) and 2-amino-benzoindole-4-ol (5.0 g, 30 mmol, CarboGen) in. The reaction mixture was stirred and heated at 95 ° C for 4.5 h and then at room temperature for 16 h. The resulting solid was collected by EtOAc (EtOAc)EtOAc. 9946i.doc -30- 1295670 NHAc (b) N-[4-(6-Alkyl-pyrimidin-4-yloxy)-benzothiazol-2-yl]-acetamide gives 4-(6-gas Base-pyrimidin-4-yloxy)-benzothiazol-2-ylamine, Example 1 (a), (4.0 g, 14 mmol), toluene (10 ml) and acetic acid liver (4.1 mL, 43

ClCl

mmol，Aldrich)混合物於85°C擾拌加熱2h，然後於室溫授 拌16h。減壓蒸發生成溶劑，並將生成之橙色固體懸浮於二 氯甲烷，過濾、收集並真空乾燥，取得灰白色固體之標題化 合物。M.p:268-275〇C 0 MS(ESI，pos. ion.) m/z: 321 (M+1)。The mixture of mmol, Aldrich) was stirred at 85 ° C for 2 h and then allowed to stir at room temperature for 16 h. Evaporation under reduced pressure gave EtOAc (EtOAc m. M.p: 268-275 〇 C 0 MS (ESI, pos. ion.) m/z: 321 (M+1).

(c)4-[6_(2 -乙酿基胺基-苯并嘆嗅-4-基氧基）-吨咬-4-基】-六 氫吡畊_1_羧酸三級丁酯 將 DMF(6 ml)與碳酸鉀（2.6 g，18.8 mmol)加入 N-[4_(6-氣 基-嘧啶-4-基氧基）-苯并噻唑-2-基]-乙醯胺，實例1(b)、（1.5 g，4.7 mmol)與六氫吡畊-1-羧酸三級丁酯（1.7 g，9.4 mmol， Fluka)混合物中。令該反應混合物於80°C攪拌加熱lh，令其 達室溫並以水（100 ml)稀釋。過濾綠色沈澱，以甲醇洗之並 真空乾燥，生成標題化合物。MS(ESI，pos· ion·) m/z: 471 (M+l) 〇 99461.doc -31- 1295670 NHAc(c) 4-[6_(2-Ethylamino-benzopyran-4-yloxy)-tonate-4-yl]-hexahydropyrrole-1_carboxylic acid tert-butyl ester DMF (6 ml) and potassium carbonate (2.6 g, 18.8 mmol) were added to N-[4_(6-methyl-pyrimidin-4-yloxy)-benzothiazol-2-yl]-acetamide, Example 1 (b), (1.5 g, 4.7 mmol) in a mixture with hexahydropyrazine-1-carboxylic acid tert-butyl ester (1.7 g, 9.4 mmol, Fluka). The reaction mixture was stirred and heated at 80 ° C for 1 h, allowed to reach room temperature and diluted with water (100 ml). The green precipitate was filtered, washed with methanol and dried in vacuo MS (ESI, pos· ion·) m/z: 471 (M+l) 〇 99461.doc -31- 1295670 NHAc

(d)N-[4-(6-六氩吡畊-〖-基-嘧啶-4-基氧基）-苯并嘆唾_2_ 基卜乙醜胺 將 TFA(15 mL，195 mmol，Aldrich)加入 〇。〇授摔下之 4-[6-(2-乙醯基胺基-苯并噻唑-4-基氧基）-嘧啶-4_基]_六氣 口比畊_1_羧酸三級丁酯、實例1(c)、（〇·45 g，0.96 mmol)之二 氣曱烧（60 ml)懸浮液。令反應混合物於室溫攪拌1 gh，添力σ 飽和NaHC03溶液終止反應，並經CH2C12萃取（2xl〇〇mL)。 令合併之有機萃取物經NazSCU乾燥，過濾並真空濃縮。將 固態之白色殘渣懸浮於MeOH，過濾並真空乾燥，生成標題 化合物 ° M.p:250.3-255.8〇C ° MS(ESI，pos· ion.) m/z: 471 (M+l) 〇(d) N-[4-(6-hexafluoropyrazine-[-yl-pyrimidin-4-yloxy)-benzoindole_2_ keb ugly amine TFA (15 mL, 195 mmol, Aldrich ) Join 〇. 4-[6-(2-Ethylamino-benzothiazol-4-yloxy)-pyrimidin-4-yl]_6-port butyl carboxylic acid tertiary butyl ester Example 1 (c), (〇·45 g, 0.96 mmol) in a gas-fired (60 ml) suspension. The reaction mixture was stirred at room temperature for 1 gh, and the reaction was quenched with EtOAc EtOAc (EtOAc). The combined organic extracts were dried over NazSCU, filtered and concentrated in vacuo. The solid white residue was suspended in MeOH, filtered and dried in vacuo to give crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

(〇N-[4_(6-{4_[(lS，lR)-l-(2•氟基-苯基）_乙基卜六氩吼味 基卜嘧啶-4_基氧基）-苯并噻唑_2_基】-乙醯胺 令異丙氧化鈦（IV)(0.14 mL，4.48 mmol，Aldrich)、N-[4-(6- 六氫吼畊-1-基-嘧啶-4-基氧基）-苯并噻唑-2-基]-乙醯胺、實 例 1(d)、（0.06 g，0.16 mmol)及 2’-氟基-苯乙酮（〇·〇3 mL，0.24 mmo卜Aldrich)之THF(0.6 mL)溶液於75°C攪拌加熱16h。令 反應混合物冷卻至-48°C，並經THF(3 ml)稀釋。添加硼氫 99461.doc -32- 1295670 化鈉（0·02 g，0.48 mmol)，並經擾拌5h令授拌之反應混合物 回溫至室溫。將MeOH(2 mL)逐滴加入混合物，並加入 NaOH(lN，50 mL)水溶液。令產物經乙酸乙酯萃取（2 X 50mL)。令合併之有機萃取物經Na2S04乾燥，過濾並真空 濃縮。令殘渣經矽膠管柱色析（梯度：〇-5%MeOH/CH2Cl2)純 化，生成淡黃色固體之標題化合物。Μ·ρ:202.6·204·3°〇。 MS(ESI，pos. ion.) m/z: 493.2 (Μ+1)。 實例2(〇N-[4_(6-{4_[(lS,lR)-l-(2•Fluoro-phenyl)-ethyl b-hexafluoroanthrylpyridin-4-yloxy)-benzo) Thiazole-2-yl]-acetamide, titanium isopropoxide (IV) (0.14 mL, 4.48 mmol, Aldrich), N-[4-(6-hexahydroindole-1-yl-pyrimidin-4-yl) Oxy)-benzothiazol-2-yl]-acetamide, Example 1 (d), (0.06 g, 0.16 mmol) and 2'-fluoro-acetophenone (〇·〇 3 mL, 0.24 mmo A solution of THF (0.6 mL) in EtOAc (0.6 mL) was stirred and stirred at 75 ° C for 16 h. The reaction mixture was cooled to -48 ° C and diluted with THF (3 ml). Add boron hydride 99461.doc -32 - 1295670 sodium (0) · 02 g, 0.48 mmol), and the reaction mixture was warmed to room temperature by stirring for 5 h. MeOH (2 mL) was added dropwise to the mixture, and NaOH (1N, 50 mL) aqueous solution was added. The combined organic extracts were dried with EtOAc EtOAc (EtOAc m. The title compound. Μ·ρ: 202.6·204·3°〇 MS (ESI, pos. ion.) m/z: 493.2 (Μ+1).

(a)4-[(lS，lR)-l_(4-氟基-苯基）_乙基】·六氩《比畊-1_羧酸三 級丁酯(a) 4-[(lS,lR)-l_(4-fluoro-phenyl)-ethyl]·hexa-argon

將異丙氧化鈦（IV)(1.9 mL，6.6 mmol，Aldrich)加入六氫 口比 _ -1 -竣酸三級丁 S旨（0.39 g，2.2 mmol，Fluka)與 4 -氣基-苯乙酮（0·39 mL，3·3 mmol，Aldrich)之THF(2 mL)溶液， 並令該反應混合物於75°C氮氣壓下攪拌18h。令混合物冷卻 至-48°C，經NaBH(OAc)3(1.23 g，6.44 mmo卜 Aldrich)與甲 醇（1 mL)處理，並令其經3.5h回溫至室溫。令反應混合物經 EtOAc(100 ml)稀釋，並經NaOH(lN，3x100 ml)水溶液洗。 分開有機層，經Na2S04乾燥，過濾並真空濃縮。令殘渣經 矽膠管柱色析（梯度：0-4% MeOH/CH2Cl2)純化，生成黃色油 之標題化合物。MS(ESI，pos· ion.) m/z: 309.2 (M+1)。 99461.doc -33- 1295670 .jC^Oh (b)l-[(lS，lR)-l_(4-氟基-苯基）_乙基】-六氩吨畊 將 TFA(0.5 mL，6.5 mmol，Aldrich)逐滴攪拌加入 0°C 之 4-[(1 S，1R)-1-(4-氟基·苯基）-乙基]-六氫。比畊-羧酸三級丁 酯、實例 2(a)、（0.42 g，1.3 6 mmol)之CH2C12(5 ml)溶液。 令該反應混合物於室溫攪拌18h並減壓蒸發。令殘渣真空乾 燥，生成粗標題化合物，其不經純化即用於下一步驟。Titanium isopropoxide (IV) (1.9 mL, 6.6 mmol, Aldrich) was added to the hexahydro port ratio _ -1 - decanoic acid tribasic butyl S (0.39 g, 2.2 mmol, Fluka) and 4-air-phenylene A solution of the ketone (0. 39 mL, 3. 3 mmol, EtOAc) (EtOAc) The mixture was cooled to -48 ° C, treated with NaHH (OAc) 3 (1.23 g, 6.44. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc) The organic layer was separated, dried over Na2EtOAc, filtered The residue was purified by EtOAc EtOAc (EtOAc:EtOAc) MS (ESI, pos. ion.) m/z: 309.2 (M+1). 99461.doc -33- 1295670 .jC^Oh (b)l-[(lS,lR)-l_(4-fluoro-phenyl)-ethyl]-hexa-argon-till TFA (0.5 mL, 6.5 mmol , Aldrich) 4-[(1 S,1R)-1-(4-fluoro-phenyl)-ethyl]-hexahydrogen at 0 ° C was added dropwise with stirring. A solution of the citric acid-tertiary butyl ester, Example 2 (a), (0.42 g, 1.36 mmol) in CH2C12 (5 ml). The reaction mixture was stirred at room temperature for 18 h and evaporated. The residue was dried <RTI ID=0.0></RTI> to <RTI ID=0.0>

NHAcNHAc

〇 (c〇N-[4_(6-{4_[(1S，1R)-1_(4-氟基-苯基）-乙基】·六氫啦畊-1-基}-嘧啶-4-基氧基）·苯并噻唑·2-基]-乙醯胺 φ 將N-[4-(6-氣基-嘧啶-4-基氧基）-苯并噻唑-2-基]-乙醯 胺、實例 1(b)、（0.25 g，0.76 mmol)與 NaHCO3(0.42 g，3.04 mmol)加入I-CGsjr)]#•氟基-苯基）_乙基μ六氫β比畊（得 自上述步驟（b)之粗產物）之DMF(4 mL)溶液。令該反應混合 物於85°C攪拌5h，冷卻至室溫並以水稀釋（2〇mL)。令反應 混合物經CH2Cl2(2x25mL)萃取，並令合併之有機萃取物經 NadCU乾燥，過遽並減壓濃縮。令殘渣經石夕膠管柱色析（梯 度：0-5% MeOH/CHWh)純化，生成白色非結晶固體之標題 99461.doc -34-〇(c〇N-[4_(6-{4_[(1S,1R)-1_(4-fluoro-phenyl)-ethyl]·hexahydro-peng-1-yl}-pyrimidin-4-yl Oxy)·benzothiazole·2-yl]-acetamide φ N-[4-(6-amphoxy-pyrimidin-4-yloxy)-benzothiazol-2-yl]-acetamide , Example 1 (b), (0.25 g, 0.76 mmol) and NaHCO3 (0.42 g, 3.04 mmol) were added to I-CGsjr)]#•Fluoro-phenyl)-ethyl μ hexahydro-β ratio tillage (from the above) A solution of the crude product of step (b) in DMF (4 mL). The reaction mixture was stirred at 85 &lt;0&gt;C for 5 h, cooled to rt and diluted with water (2 EtOAc). The reaction mixture was extracted with EtOAc (EtOAc m. The residue was purified by silica gel column chromatography (gradient: 0-5% MeOH/CHWh) to give the title of white amorphous solid. 99461.doc -34-

1295670 化合物。M.p.:247.3〇C 0 MS(ESI，pos. ion.) m/z: 493 (Μ+1) 〇 另外實例 下列實例係由N-[4-(6-氣基-嘧啶-4-基氧基）-苯并噻唑-2-基]-乙醯胺（實例1(b))，根據製備實例2所述之一般方法，或 對其做些微修正製成：1295670 Compound. Mp: 247.3 〇C 0 MS (ESI, pos. ion.) m/z: 493 (Μ+1) 〇Additional Examples The following examples are from N-[4-(6-carbyl-pyrimidin-4-yloxy) - benzothiazol-2-yl]-acetamide (Example 1 (b)), according to the general method described in Preparation Example 2, or slightly modified:

實例 結構 M.S. (ESI) m/z 熔點(°C) 3 丄 NHAc 543 (M+l) 153.4-154.5 4 丄 NHAc N^N 555 (M+l) 238-240 5 1 NHAc 广丫人N) . N〆 Nv^N 507 (M+l) 231.1-232.5 6 丄 NHAc N^N 505 (M+l) 151 7 /_ 7 ? NHAc θγ^°γ4^8 N^N 521 (M+l) 218.9-219.7 8 f ? NHAc N^&lt; N^N 521 (M+l) 196.6-196.7 99461.doc -35- (S) 1295670Example Structure MS (ESI) m/z Melting Point (°C) 3 丄NHAc 543 (M+l) 153.4-154.5 4 丄NHAc N^N 555 (M+l) 238-240 5 1 NHAc 广丫人N) . N〆Nv^N 507 (M+l) 231.1-232.5 6 丄NHAc N^N 505 (M+l) 151 7 /_ 7 ? NHAc θγ^°γ4^8 N^N 521 (M+l) 218.9- 219.7 8 f ? NHAc N^&lt; N^N 521 (M+l) 196.6-196.7 99461.doc -35- (S) 1295670

9 ? ? NHAc N^N 507 (M+l) 211.6-215.8 10 丄? NHAc ^nyv°y^ys Nv^N 507 (M+l) 212.2-212.5 11 丄 NHAc F〇c〇w^ Nv^N 511 (M+l) 256-268 12 丄 NHAc C1xrow〇^s 509 (M+l) 242-250 13 1 NHAc 493 (M+l) 204 14 丄 NHAc Fxr〇w κ 507 (M+l) 232-234 15 1 NHAc N^N 481 (M+l) 135-140 16 1 NHAc s^〇Wris N^&gt;N 481 (M+l) 137.5-142.4 17 ^ I NHAc ^ 〇NYV°Ws Nv^N 465 (M+l) 138.6-139.7 99461.doc -36- 1295670 18 1 NHAc Nv^N 561 (M+l) 135-141 19 丄 NHAc U O^o^s 474 (M+l) 278.1-278.5 20 I NHAc ^ ^nyv0Vys N^N 515 (M+l) 217.4-218.59 ? ? NHAc N^N 507 (M+l) 211.6-215.8 10 丄? NHAc ^nyv°y^ys Nv^N 507 (M+l) 212.2-212.5 11 丄NHAc F〇c〇w^ Nv^N 511 (M+l) 256-268 12 丄NHAc C1xrow〇^s 509 (M+l) 242-250 13 1 NHAc 493 (M+l) 204 14 丄NHAc Fxr〇w κ 507 (M+l) 232- 234 15 1 NHAc N^N 481 (M+l) 135-140 16 1 NHAc s^〇Wris N^&gt;N 481 (M+l) 137.5-142.4 17 ^ I NHAc ^ 〇NYV°Ws Nv^N 465 (M+l) 138.6-139.7 99461.doc -36- 1295670 18 1 NHAc Nv^N 561 (M+l) 135-141 19 丄NHAc UO^o^s 474 (M+l) 278.1-278.5 20 I NHAc ^ ^nyv0Vys N^N 515 (M+l) 217.4-218.5

實例21Example 21

(a)4-[(lS)-l-(4-氟基-苯基）-乙基]-六氫17比畊-1-羧酸三級丁 酯與4-[(lR)-l-(4-氟基·苯基）-乙基]-六氫咕畊-1-羧酸三級 丁酯。4-[(lS，lR)-l-(4-氟基-苯基）-乙基]-六氫井-1-基-緩酸三級丁酯、實例2(a)、（1.29 g，4.2 mmol)之二個對掌 體係藉由掌型 HPLC(100%MeOH/0.08%AcOH/0.02%三乙胺） 分開。收Ι曾 ， I弟一個部分並真空濃縮而產生淡黃色油之 4-[(lS)小u 氣基-苯基）-乙基]-六氫吡畊-1-羧酸三級丁 酷。收取筮 _ 乐二個部分並真空濃縮而產生淡黃色油之 4-[(lR)-l-(4 &amp;诖 、氣基-笨基）-乙基]-六氫吡畊-1-羧酸三級丁酯。 99461.doc -37- 1295670 三 NHAc(a) 4-[(lS)-l-(4-Fluoro-phenyl)-ethyl]-hexahydro 17-tert-l-carboxylic acid tert-butyl butyl ester with 4-[(lR)-l- (4-Fluoro-phenyl)-ethyl]-hexahydroindole 1-carboxylic acid tert-butyl ester. 4-[(lS,lR)-l-(4-Fluoro-phenyl)-ethyl]-hexahydro-n-yl-s-acid tri-butyl butyl ester, Example 2 (a), (1.29 g, The two palms of 4.2 mmol) were separated by palm-type HPLC (100% MeOH / 0.08% AcOH / 0.02% triethylamine). Ι Ι , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 4-[(lR)-l-(4 &amp;诖, gas-phenyl)-ethyl]-hexahydropyrrol-1-carboxylate is obtained by charging the two parts of 筮_乐 and concentrating in vacuo to give a pale yellow oil. Butyl tertiary butyl ester. 99461.doc -37- 1295670 three NHAc

Ν^Ν (b)N-[4-(6-{4_[(lS)-l-(4-氣基-苯基）-乙基]-六氮 11 比呼-1· 基}-喂σ定-4-基氧基）_苯并U塞σ坐-2-基]-乙龜胺。 將 TFA(0.5 mL，6.5 mmol，Aldrich)於 0°C 擾拌下加入 4-[l(S)-(4-氟基-苯基）·乙基]-六氫ϋ比π井-卜竣酸三級丁醋、實 例21(&amp;)、（0.42§，1.3 5 111111〇1)之(：112(：12(2 1111^)懸浮液。令反 應混合物於室溫攪拌18h並減壓蒸發。溶殘渣於DMF(3 mL)，並於該溶液添加N-[4-(6-氯基-嘧啶-4-基氧基）-苯并噻 嗤-2-基]-乙醯胺、實例i(b)、（0.43 g，1.35 mmol)與破酸絶 (1.3 g，4·05 mmol)。令反應混合物於85°C攪拌加熱，並藉 TLC(5% MeOH/CH^Ch)偵測反應之進行。反應完成後，令 混合物冷卻至室溫並以水稀釋（40 mL)。將生成之淡黃色固 體過濾並真空乾燥。令固體經矽膠管柱色析（梯度：〇_5% MeOH/CH2Cl2)純化，生成非結晶白色固體之標題化合物。 M.p.:243.6-245.7〇C 0 MS(ESI，pos· ion·) m/z: 493 (M+1) 〇 實例22Ν^Ν (b) N-[4-(6-{4_[(lS)-l-(4-carbyl-phenyl)-ethyl]-hexanitrogen 11-hept-1·yl}-feed σ Din-4-yloxy)-benzo-U-sigma-pyridyl-2-yl]-methanamine. Add TFA (0.5 mL, 6.5 mmol, Aldrich) at 0 ° C to add 4-[l(S)-(4-fluoro-phenyl)ethyl]-hexahydropyrene to π well-di Acidic tertiary butyl vinegar, Example 21 (&amp;), (0.42 §, 1.3 5 111111 〇 1) (: 112 (: 12 (2 11 11 )) suspension. The reaction mixture was stirred at room temperature for 18 h and evaporated under reduced pressure. The residue was dissolved in DMF (3 mL), and N-[4-(6-chloro-pyrimidin-4-yloxy)-benzothiazol-2-yl]-acetamide was added to the solution. i(b), (0.43 g, 1.35 mmol) and acid-destroy (1.3 g, 4.05 mmol). The reaction mixture was stirred and heated at 85 ° C and was taken by TLC (5% MeOH/CH^Ch) The reaction was carried out. After the reaction was completed, the mixture was cooled to room temperature and diluted with water (40 mL). The pale yellow solid which was formed was filtered and dried in vacuo. The solid was filtered on a gel column (gradient: 〇_5% MeOH /CH2Cl2) was purified to give the title compound as a white solid. Mp: 243.6-245.7 〇 C 0 MS (ESI, pos· ion·) m/z: 493 (M+1) 〇 Example 22

NHAc N=\NHAc N=\

N^N N-[4-(6_{4-[(lR)-l-(4 -氟基—苯基）-乙基]-六氫吼_ _i_基卜 鳴咬-4-基氧基）-苯并嗟唾-2-基]-乙醯胺。根據實例21(b)所 99461.doc -38- 1295670 述方法，4_[(1R)-1_(4_氟基·苯基）-乙基]-六氫吼畊-丨_羧酸三 級丁酯、實例 21(a)、（〇·48 g，1.6 mmol)與 N_[4-(6-氣基哺 啶_4_基氧基）-苯并噻唑_2_基]-乙醯胺、實例1(b)、（0.512 g， 1.6 mmol)提供白色固體之標題化合物。Μ·ρ·:243.8-245.9 C。MS(ESI，p〇s· ion·) m/z: 493 (M+1) 0 實例23N^N N-[4-(6_{4-[(lR)-l-(4-fluoro-phenyl)-ethyl]-hexahydroindole__i_) )-benzopyrene-2-yl]-acetamide. According to the method of Example 21(b), 99461.doc -38-1295670, 4_[(1R)-1_(4-fluorophenyl)-ethyl]-hexahydroindole-indole-carboxylic acid tertiary butyl Ester, Example 21(a), (〇·48 g, 1.6 mmol) and N_[4-(6-azepine-4-yloxy)benzothiazol-2-yl]-acetamide, Example 1 (b), (0.512 g, 1.6 mmol) Μ·ρ·: 243.8-245.9 C. MS (ESI, p〇s· ion·) m/z: 493 (M+1) 0 Example 23

(a)8-(6-氣基-嘧啶-4-基氧基）-喹啉-2-基胺 將碳酸鉀（1 ·9 g，13.6 mmol)加入5 Ο-mL之含有4,6-二氯基 哺啶（〇·5 g，3.4 mmol，Aldrich)與 2-胺基-8·羥基喹啉（0·54 g，3·4 mmol，Sigma)與DMF(4 ml)的圓底燒瓶。令懸浮液 於氣氣壓下7 5 C授摔5 h。令反應混合物冷卻至室溫，以水 稀釋（50 mL)並經CH2C12(2x75 mL)萃取。令合併之有機萃取 物經NazSO4乾燥，過濾並真空濃縮。令殘渣經石夕膠管柱色 析（梯度：0-50% EtOAc/己烷）純化，生成白色固體之標題化 合物。M.p.:185-186°C。MS(ESI，P〇s· i〇n·) m/z: 273 (M+1)。(a) 8-(6-Alkyl-pyrimidin-4-yloxy)-quinolin-2-ylamine Addition of potassium carbonate (1·9 g, 13.6 mmol) to 5 Ο-mL containing 4,6- Round bottom flask of dichloro-naphthyridine (〇·5 g, 3.4 mmol, Aldrich) and 2-amino-8-hydroxyquinoline (0·54 g, 3.4 mmol, Sigma) and DMF (4 ml) . Let the suspension drop for 5 h at 7 5 C under air pressure. The reaction mixture was cooled to room temperature, diluted with water (50 mL) andEtOAc. The combined organic extracts were dried over NazSO4, filtered and evaporated. The residue was purified with EtOAc EtOAc (EtOAc:EtOAc: M.p.: 185-186 °C. MS (ESI, P〇s· i〇n·) m/z: 273 (M+1).

(b)l-[(lR)-l-(4_氟基-苯基）_乙基](甲苯黃基六氫〇比 畊。令N，N-雙（2-氣乙基）-對·甲笨磺胺（技術上為9〇%，a』 99461.doc -39- 1295670 g，158 mmol，Lancaster)與（1R)-1_(4·氟苯基）乙胺（20 g， 144 mmol，SynQuest)N，N-二異丙基乙胺（50 mL)之混合物於 氮氣壓下125°C攪拌加熱18h。令反應混合物冷卻至100°C以 下，並經攪拌緩慢添加7/3之Et0H/H20混合物（120mL)。令 該反應混合物達室溫，並繼續攪拌2.5h。過濾固體沈澱物， 並以H2O(3x50 mL)與己烷（2x50 mL)洗之。令該固體於50°C 真空乾燥18h，並於1:1之Et0H/H20混合物（140 mL)攪拌 75min。過濾固體沈澱物，並以1:1之Et0H/H20混合物（40 mL) 與7:3之Et0H/H20混合物（20 mL)洗之，並於50°C真空乾燥 6h，生成灰白色固體之標題化合物。MS(ESI，pos. ion.) m/z: 363 (M+l) 〇(b) l-[(lR)-l-(4-fluoro-phenyl)-ethyl](tolyl-ylhexahydroindole-specific tillage. Let N,N-bis(2-gasethyl)-pair · sulfosulfonamide (technically 9〇%, a) 99461.doc -39- 1295670 g, 158 mmol, Lancaster) and (1R)-1_(4·fluorophenyl)ethylamine (20 g, 144 mmol, SynQuest) A mixture of N,N-diisopropylethylamine (50 mL) was stirred and heated under a nitrogen pressure at 125 ° C for 18 h. The reaction mixture was cooled to below 100 ° C, and 7/3 of Et0H/ was slowly added with stirring. H20 mixture (120 mL). The reaction mixture was taken to room temperature and stirring was continued for 2.5 h. The solid precipitate was filtered and washed with H2O (3×50 mL) and hexane (2×50 mL). Dry for 18 h and stir for 7.5 min in 1:1 Et0H / H20 mixture (140 mL). The solid precipitate was filtered and mixed with 1:1 Et0H/H20 (40 mL) and 7:3 Et0H/H20 (20) The title compound was obtained as an off-white solid. MS (ESI, pos. ion.) m/z: 363 (M+l) 〇

(c)l-[(lR)-l-(4-氣基-苯基）-乙基]-六氯处呼。令 1 - [(1R) -1 - (4-氣基-苯基）-乙基]-4-(甲苯-4_石黃基）·六氣°比 畊、實例23(b)、（20 g，55 mmol)、4-羥基苄酸（22.9 g，166 mmo卜 Aldrich)與 HBr之 AcOH(33 wt%，200 mL，Aldrich) 溶液的混合物於室溫氮氣壓下攪拌加熱48h。緩慢添加水 (200 mL)，並令該混合物於室溫攪拌2h。濾出固體沈澱物， 並以H2O(2x5 0 mL)洗該濾塊。合併濾液與水洗液並以甲苯 萃取（4 X 50 mL)。令水相於冰浴中冷卻，並以分批之 KOH(23 5g)處理直至pH&gt; 10。以甲苯（3x50 mL)與乙酸乙酯 (50 mL)萃取水性溶液。以鹽液（100 mL)洗合併之有機萃 99461.doc -40- 1295670 取物’經MgSCU乾燥，過濾並減壓濃縮。令殘渣經真空乾 燥’生成淡棕色固體之標題化合物。MS(ESI，pos. ion.) m/z: 209 (M+1)〇(c) l-[(lR)-l-(4-carbyl-phenyl)-ethyl]-hexachlorohethane. Let 1 - [(1R) -1 - (4-carbyl-phenyl)-ethyl]-4-(toluene-4_石黄基)·six gas ratio tillage, examples 23(b), (20 A mixture of g, 55 mmol), 4-hydroxybenzyl acid (22.9 g, 166 mmo, Aldrich) and HBr in AcOH (33 wt%, 200 mL, Aldrich) was stirred and stirred at room temperature under nitrogen for 48 h. Water (200 mL) was added slowly and the mixture was stirred at room temperature for 2 h. The solid precipitate was filtered off and the filter was washed with H.sub.2 (2×50 mL). The filtrate and water wash were combined and extracted with toluene (4 X 50 mL). The aqueous phase was allowed to cool in an ice bath and was worked up in portions KOH (23 5 g) until pH &gt; The aqueous solution was extracted with toluene (3 x 50 mL) and ethyl acetate (50 mL). The combined organic extracts were washed with a brine (100 mL) and dried. The residue was dried in vacuo to give the title compound as a pale brown solid. MS (ESI, pos. ion.) m/z: 209 (M+1)〇

(d)8-(6-{4-[(lR)-(4-氟基-苯基）_乙基]-六氫α比畊_i-基卜喷 淀-4-基氧基）-喹琳-2-基胺。將碳酸卸（〇·7 g，2·2 mmol)加 入l-[(lR)-(4-l基-苯基）乙基]-六氫ϋ比n井、實例23(e)(〇.i5 g，0.72 mmol)與8-(6-氣基-嘧啶-4-基氧基）-喹啉_2_基胺、 實例 23(a)、（0.19 g，0·72 mmol)之 DMF(4 mL)溶液，並令 反應混合物於氮氣下85°C攪拌加熱8h。令反應混合物達到 室溫，並以水（20 mL)稀釋。過濾生成之灰白固體，並溶於 CH2C12(20 mL) 〇 令該溶液經水（2x50 mL)洗，Na2S04乾燥， 過濾並減壓蒸發。令殘渣經矽膠管柱色析（梯度：0-5% MeOH/CH2Cl2)純化，然後於EtOAc/己烷再結晶，生成白色 固體之標題化合物。MS(ESI, pos· ion·) m/z: 445 (M+1)。 實例24(d) 8-(6-{4-[(lR)-(4-Fluoro-phenyl)-ethyl]-hexahydro-α ratio tillage_i-kib spray-4-yloxy)- Quinolin-2-ylamine. Carbonate unloading (〇·7 g, 2.2 mmol) was added to l-[(lR)-(4-l-phenyl-ethyl)ethyl]-hexahydropyrene than n well, Example 23(e) (〇. I5 g, 0.72 mmol) with 8-(6-methyl-pyrimidin-4-yloxy)-quinolin-2-ylamine, Example 23 (a), (0.19 g, 0·72 mmol) DMF ( 4 mL) solution, and the reaction mixture was stirred and heated at 85 ° C for 8 h under nitrogen. The reaction mixture was allowed to reach room temperature and diluted with water (20 mL). The resulting white solid was filtered and dissolved in CH2C12 (20 mL) EtOAc (EtOAc) The residue was purified by EtOAc EtOAc (EtOAc:EtOAc: MS (ESI, pos· ion·) m/z: 445 (M+1). Example 24

8-(6-{4-[(lSH4-氟基-苯基）-乙基]•六氫°比畊-l-基}-嘧啶 -4·基氧基）-喹啉·2_基胺。令l-[(lS)-(4-氟基·苯基）-乙基]_ 六氫吡畊（〇·15 g，0.72 mmo卜由（lS)-l-(4•氟基-苯基）_乙胺 99461.doc -41- 1295670 (SynQuest)根據實例23步驟（b)與（c)製成）與8-(6-氯基-嘧啶 -4-基氧基）-喹啉-2_基胺（0.19 g，0.72 mmol)於實例23(d)之 條件下進行反應，生成白色固體之標題化合物。M.P.: 167 〇C 0 MS(ESI，pos. ion.) m/z: 445 (M+1) 〇 實例25 ώΝ〇2 nh2 (a) 3·甲氧基-2_硝基-苯胺令2-胺基_3_硝基酚（25.0 g，162 mmol，Aldrich)與 K2C〇3(27 g，195 mmol)之 DMF(65 ml)混 合物於室溫攪拌lh。添加碘化甲烷（12.2 mL，195 mmol， Aldrich)，並令該反應於室溫攪拌30h。令反應經H20稀釋， 並經EtOAc(3x)萃取。令合併之有機層經Na2S04乾燥，過濾 並真空濃縮。令暗紅色固體經己烷再結晶，生成橙色針狀 之標題化合物。MS(ESI，pos. ion.) m/z: 169 (M+1)。 \〇 rVH2 U · h2s〇4 ^^nh2 (b) 3-甲氧基-苯-1，2-二胺硫酸鹽。令3-甲氧基-2-硝基-苯 胺、實例25(a)、（4·6 g，27 mmol)、鐵粉（10.7 g，191 mmol， Aldrich)、EtOH(130 mL)與 H2O(10 mL)混合物於 50°C 加熱。 攪拌下逐滴添加HC1(12.1 Μ ，1.7 mL)溶液。令混合物廻 流加熱3h，並令其冷卻至室溫。經NaOH中和並濾過Celite® 99461.doc -42- 1295670 後真空去除溶劑，並令殘渣於CH2C12與飽和NaHC03水溶液 之間進行區分。經CH2C12(3x)萃取後，濃縮合併之有機層。 將殘渣再溶於EtOH(30 mL)，並經濃H2S04處理，直至不再 有沈澱物形成。過濾去除生成之固體，經EtOH洗並於室溫 真空乾燥20h，生成灰白色粉末之標題化合物。MS(ESI，pos. ion·) m/z·· 139(M-HSO〇 〇8-(6-{4-[(lSH4-Fluoro-phenyl)-ethyl]•hexahydrogen ratio tillage-l-yl}-pyrimidin-4-yloxy)-quinoline·2-amine . Let l-[(lS)-(4-fluorophenyl)-ethyl]_ hexahydropyridine (〇·15 g, 0.72 mmo from (lS)-l-(4•fluoro-phenyl) )-ethylamine 99461.doc -41- 1295670 (SynQuest) according to Example 23, steps (b) and (c), and 8-(6-chloro-pyrimidin-4-yloxy)-quinoline-2 The title compound was obtained as a white solid. MP: 167 〇C 0 MS(ESI, pos. ion.) m/z: 445 (M+1) 〇 Example 25 ώΝ〇2 nh2 (a) 3·methoxy-2-nitro-aniline 2- A mixture of the amine _3_nitrophenol (25.0 g, 162 mmol, EtOAc) and EtOAc (EtOAc) Methyl iodide (12.2 mL, 195 mmol, Aldrich) was added and the mixture was stirred at room temperature for 30 h. The reaction was diluted with H20 and EtOAc (EtOAc) The combined organic layers were dried with EtOAc (EtOAc)EtOAc. The dark red solid was recrystallized from hexane to give the title compound. MS (ESI, pos. ion.) m/z: 169 (M+1). \〇 rVH2 U · h2s〇4 ^^nh2 (b) 3-methoxy-benzene-1,2-diamine sulfate. 3-methoxy-2-nitro-aniline, Example 25(a), (4.6 g, 27 mmol), iron powder (10.7 g, 191 mmol, Aldrich), EtOH (130 mL) and H2O ( 10 mL) The mixture was heated at 50 °C. A solution of HCl (12.1 Μ, 1.7 mL) was added dropwise with stirring. The mixture was heated to reflux for 3 h and allowed to cool to room temperature. After neutralizing with NaOH and filtering through Celite® 99461.doc -42-1295670, the solvent was removed in vacuo and the residue was partitioned between CH2C12 and saturated aqueous NaHC03. After extraction with CH2C12 (3x), the combined organic layers were concentrated. The residue was redissolved in EtOH (30 mL) and concentrated over H.sub.2SO. The resulting solid was filtered, washed with EtOAc (EtOAc) MS (ESI, pos. ion·) m/z·· 139 (M-HSO〇 〇

(c)3-胺基-8-甲氧基-1H-喹嘮啉-2-酮與3-胺基-5-曱氧基 -1H-喹嘮啉-2-酮。將 NaHC03(1.68 g，20 mmol，JT Baker) 加入3-甲氧基-苯·1，2_二胺硫酸鹽、實例25(b)(2.36 g，10 mmol)之EtOH(15 mL)與H2O(10mL)懸浮液。當產氣完成 時，添加乙氧基-亞胺基-乙酸乙酯（1.6 g，11 mmol，根據J· Chem. Soc. Perkin. Trans. 1，1999，1789製成），並令該混合 物於室溫攪拌16h。令反應經飽和NaHC03水溶液稀釋，並 經25%之i-PrOH/CHCl3萃取（5x)。令合併之有機層經Na2S04 乾燥，過濾並真空濃縮。經矽膠管柱色析（梯度：0-5% MeOH/CH2Cl2)純化，提供淡棕色粉末之3-胺基-8-甲氧基 -1H-喹噚啉 _2·酮[MS(ESI，pos· ion·) m/z: 192 (M+1)]及 3-胺 基-5-甲氧-1H-喳喏啉_2_酮之淡棕色粉末[MS(ESI，pos. ion.) m/z: 192 (M+1)]。 99461.doc -43- 1295670(c) 3-Amino-8-methoxy-1H-quinoxalin-2-one and 3-amino-5-nonyloxy-1H-quinoxalin-2-one. Add NaHC03 (1.68 g, 20 mmol, JT Baker) to 3-methoxy-benzene·1,2-diamine sulfate, Example 25(b) (2.36 g, 10 mmol) of EtOH (15 mL) and H2O (10 mL) suspension. When the gas production was completed, ethoxy-imino-ethyl acetate (1.6 g, 11 mmol, made according to J. Chem. Soc. Perkin. Trans. 1, 1999, 1789) was added and the mixture was allowed to Stir at room temperature for 16 h. The reaction was diluted with saturated aqueous NaHCO.sub.3 and extracted with &lt;RTI ID=0.0&gt;&gt; The combined organic layers were dried with EtOAc EtOAc m. Purified by a ruthenium gel column chromatography (gradient: 0-5% MeOH/CH.sub.2Cl.sub.2) to afford 3-amino-8-methoxy-1H-quinoxaline-2·one as a light brown powder [MS (ESI, pos) · ion·) m/z: 192 (M+1)] and light yellow powder of 3-amino-5-methoxy-1H-carboline-2-one [MS (ESI, pos. ion.) m /z: 192 (M+1)]. 99461.doc -43- 1295670

(d)3 -胺基-5-經基-1H-哇'^亏淋_2_酮。將 aici3(〇97 g，74 mmol，Aldrich)加入3-胺基-5_甲氧基_ih_啥tr号啦_2_酮、實 例25(c)、（0.47 g，2.5 mmol)之苯（25 mL)懸浮液，並令混合 物擾择迴流加熱2h。令反應混合物冷卻至室溫，並小心添 加飽和NaHCCh溶液。令生成之混合物經25%之 i-PrOH/CHCh萃取（5x)。令合併之有機萃取物經Na2S〇4乾 燥，過濾並真空濃縮，提供棕色粉末。MS(ESI，pos. ion.；) m/z: -178 (M+l) 〇(d) 3-Amino-5-trans-yl-1H-who's depleted _2-one. Add aici3 (〇97 g, 74 mmol, Aldrich) to 3-amino-5-methoxy-ih_啥tr No. 2 ketone, Example 25 (c), (0.47 g, 2.5 mmol) benzene (25 mL) of the suspension and the mixture was heated under reflux for 2 h. The reaction mixture was allowed to cool to room temperature and a saturated NaHCCh solution was carefully added. The resulting mixture was extracted with 25% i-PrOH/CHCh (5x). The combined organic extracts were dried with EtOAc (EtOAc m. MS (ESI, pos. ion.;) m/z: -178 (M+l) 〇

(e)4 -氣基- 6-{4-[(lS，l R)-1-(4-氟基-苯基）_乙基]-六氫α比π井 -1_基}_喊淀。令1-[(1S，1R)-1-(4_1基·苯基）-乙基]-六氫α比 畊、實例2(b)、（0.87 g，4·2 mmol)與4,6-二氣基嘧啶（0.7 g， 4·6 mmol，Aldrich)於實例1(c)所述條件下進行反應，生成 白色固體之標題化合物。MS(ESI，pos. ion·) m/z: 321 (M+l) 〇 99461.doc -44- 1295670(e) 4 - gas group - 6-{4-[(lS,l R)-1-(4-fluoro-phenyl)-ethyl]-hexahydro-α ratio π well-1_ base}_ shout Dian. Let 1-[(1S,1R)-1-(4_1-ylphenyl)-ethyl]-hexahydro-α ratio tillage, Example 2(b), (0.87 g, 4·2 mmol) and 4,6- The di- fluoropyrimidine (0.7 g, 4·6 mmol, Aldrich) was taken to give the title compound as a white solid. MS (ESI, pos. ion·) m/z: 321 (M+l) 〇 99461.doc -44- 1295670

(f)3-胺基-5-(6-{4-[(lS，lR)-l-(4-氟基-苯基）-乙基]-六氫咕 畊-1-基卜嘧啶-4·基氧基）·1Η-喹嘮啉-2-酮。令4-氯基 -6-{4-[(lS，lR)_l_(4-氟基-苯基）-乙基]-六氫α比畊-i-基}-嘧 咬、實例25(e)、（0.18 g，0·56 mmol)、3-胺基-5-經基-1Η-喹嘮啉 _2_酮、實例 25(d)、（0.10 g，0.56 mmol)與 K2CO3(0.12 g，〇·85 mmol，Aldrich)之DMF(5mL)混合物於80°C 攪拌加 熱24h。冷卻至室溫後，添加cS2CO3(0.36 g，1·1 mmol， Aldrich)，並令該混合物於90°C攪拌96ll。令該混合物冷卻 至室溫，經H20稀釋，並經25%之i-Pr〇H/CHCl3萃取（5x)。 令合併之有機萃取物經Na2S04乾燥，過濾並真空濃縮。令 殘渣經矽膠管柱色析（梯度：〇-5% (2M NH3之MeOH)/CH2Cl2) 純化’提供白色非結晶粉末之標題化合物。MS(ESI，p〇s· ion.) m/z: 462.2 (M+l) 〇 實例26(f) 3-Amino-5-(6-{4-[(lS,lR)-l-(4-fluoro-phenyl)-ethyl]-hexahydroindol-1-ylpyrimidine- 4·yloxy)·1Η-quinoxalin-2-one. 4-chloro-6-{4-[(lS,lR)_l_(4-fluoro-phenyl)-ethyl]-hexahydro-α than plough-i-yl}-pyrimidine, Example 25 (e ), (0.18 g, 0·56 mmol), 3-amino-5-carbyl-1Η-quinoxaline-2-one, Example 25(d), (0.10 g, 0.56 mmol) and K2CO3 (0.12 g) A mixture of DMF (5 mL) of 〇·85 mmol, Aldrich) was stirred and stirred at 80 ° C for 24 h. After cooling to room temperature, cS2CO3 (0.36 g, 1.1 mmol, Aldrich) was added, and the mixture was stirred at 90 ° C. The mixture was allowed to cool to room temperature, diluted with H.sub.2, and extracted with &lt;RTI ID=0.0&gt;&gt; The combined organic extracts were dried with EtOAc EtOAc m. The residue was purified by column chromatography (gradient: EtOAc - EtOAc (EtOAc: EtOAc) MS (ESI, p〇s· ion.) m/z: 462.2 (M+l) 实例 Example 26

(a)3-胺基-5-(6-氣基·嘧啶基甲基）_1H_喹呤啉酮。將 K2CO3(0.33 g’ 2·4 mmol，Aldrich)加入4,6_二氣基嘧啶（0·3 0 g ’ 2·0 mmol ’ Aldrich)與 3-胺基-5-羥基-1Η_ 喹嘮啉-2-酮、 99461.doc -45- 1295670 實例 25(d)、（0·35 g，2.0 mmol)之DMF(10 mL)溶液，並令 該混合物於室溫攪拌24h。令該反應混合物經H2〇稀釋，並 過渡淡棕色固體沈澱物。以H2〇洗遽塊並風乾·，生成標題化 合物。MS(ESI，pos· ion·) m/z: 290·1 (M+1)。(a) 3-Amino-5-(6-a)pyrimidylmethyl)_1H_quinoxalinone. K2CO3 (0.33 g' 2·4 mmol, Aldrich) was added to 4,6-dioxapyrimidine (0.30 g '2.0 mmol 'Aldrich) and 3-amino-5-hydroxy-1Η_quinoxaline 2-ketone, 99461.doc -45 - 1295670 Example 25 (d), (0.35 g, 2.0 mmol The reaction mixture was diluted with H.sub.2 and a pale brown solid precipitate was obtained. The block was washed with H2 and air dried to give the title compound. MS (ESI, pos· ion·) m/z: 290·1 (M+1).

(b)3_胺基- 5- (6-{4-[(l R)· 1-(4 -氣基-苯基）_乙基]_六氯σ比呼 -l-基}-嘧啶-4-基氧基）-1Η-喹噚啉-2-酮。將3-胺基_5-(6-氣 基·嘧啶_4_基甲基）-1Η-喹吟啉-2-酮、實例26(a)、（0.17 g， 0.59 mmol)與l-[(lR)-l-(4-氟基-苯基）-乙基]-六氫井、實 例 23(c)、（0.12 g，0·59 mmol)混合物溶於 DMF(5mL)。添加 Cs2CO3(0.38 g，1.2 mmol)於此溶液，並令該混合物於85°C 攪拌加熱8h。令該反應混合物冷卻至室溫，經H20稀釋，並 過濾固體沈澱物。以H2〇洗濾塊，並經矽膠管柱色析（梯 度：0-5% (2M NH3iMeOH)/CH2Cl2)純化，生成灰白色固體 之標題化合物。Mp:292.2_293.9°C。MS(ESI，pos· ion·) m/z: 462.2 (M+l) 〇 實例27 99461.doc -46-(b) 3-amino- 5-(6-{4-[(l R)· 1-(4-carbo-phenyl)-ethyl]-hexachloro-pyridyl-h-l-yl}-pyrimidine 4--4-yloxy)-1Η-quinoxalin-2-one. 3-Amino-5-(6-carbyl.pyrimidin-4-ylmethyl)-l-quinoxalin-2-one, Example 26(a), (0.17 g, 0.59 mmol) and l-[ (lR)-l-(4-Fluoro-phenyl)-ethyl]-hexahydro well, Example 23 (c), (0.12 g, 0. 59 mmol) mixture was dissolved in DMF (5 mL). Cs2CO3 (0.38 g, 1.2 mmol) was added to this solution, and the mixture was stirred and stirred at 85 ° C for 8 h. The reaction mixture was allowed to cool to room temperature, diluted with H20 and filtered. The filter was washed with H.sub.2, and purified by EtOAc (EtOAc:EtOAc) Mp: 292.2_293.9 °C. MS (ESI, pos· ion·) m/z: 462.2 (M+l) 〇 Example 27 99461.doc -46-

12956701295670

3-胺基-5_(6_{4-[(lS)-l-(4-氟基-苯基）_乙基μ六氫σ比畊_卜 基}-嘴咬_4-基氧基）·ιη_喹嘮啉-2-酮。該材料係根據實例 26(b)所述方法，藉3-胺基-5-(6-氣基-嘧啶-4-基甲基）-1Η-啥 4 淋-2,、實例 26(a)、（0.20 g，0.69 mmol)與 1-[(IS)-1-(4-氟基-笨基）_乙基]_六氫吡畊（〇·14 g，0·69 mmol，根據實例 23步驟（b)與（c)由（is)_l_(4·氟苯基）乙胺（SynQuest)製成）反 應製成。分離灰白色固體之標題化合物。Mp:294.5-295.3 〇C 0 MS(ESI，pos· ion·) m/z: 462.2 (M+1)。 實例283-amino-5-(6_{4-[(lS)-l-(4-fluoro-phenyl)-ethyl] hexahydro σ ratio tillage_b base}-mouth bite_4-yloxy) · ηη_quinoxalin-2-one. This material was subjected to the method described in Example 26 (b) by 3-amino-5-(6-a)-pyrimidin-4-ylmethyl)-1Η-啥4 -2, Example 26(a) , (0.20 g, 0.69 mmol) and 1-[(IS)-1-(4-fluoro-p-phenyl)-ethyl]-hexahydropyrazine (〇·14 g, 0·69 mmol, according to Example 23 Steps (b) and (c) are prepared by reacting (is)_l_(4.fluorophenyl)ethylamine (SynQuest). The title compound was isolated as an off white solid. Mp: 294.5-295.3 〇C 0 MS (ESI, pos· ion·) m/z: 462.2 (M+1). Example 28

(a)7-(6-氣基嘧啶-4-基氧基）喹琳。令羥基喹琳（〇 387 g， 2.67 mmol，Acros)、4,6-二氣基嘧啶（0·398 g，2.67 mmol， 八1(1士11)與碳酸卸（0.369 £，2.67 111111〇1，八1(114〇11)之〇]\^(3 1111^) 混合物於室溫攪拌16h，然後在微波爐合成器中以i〇〇〇c加 熱5min。令該反應混合物冷卻至室溫並過濾。令濾塊經曱 醇洗（5mL)，並減壓濃縮渡液。令該紅棕色殘渣經石夕膠管柱 色析（梯度：0-50% EtOAc/己烷）純化，提供淡黃色非結晶固 體之標題化合物。MS(ESI，p〇s. i〇n ) m/z: 258 (M+1)。 99461.doc -47- 1295670(a) 7-(6-Gasylpyrimidin-4-yloxy)quinolin. Hydroxyquinoline (〇387 g, 2.67 mmol, Acros), 4,6-dioxapyrimidine (0·398 g, 2.67 mmol, 八1 (1士11) and carbonic acid unloading (0.369 £, 2.67 111111〇1) , 8:1 (114〇11) 〇]\^(3 1111^) The mixture was stirred at room temperature for 16 h, then heated in a microwave synthesizer for 5 min at i〇〇〇c. The reaction mixture was cooled to room temperature and filtered. The filter was washed with decyl alcohol (5 mL) and concentrated under reduced pressure. The red-brown residue was purified by chromatography ( gradient: 0-50% EtOAc/hexane) MS (ESI, p〇s. i〇n) m/z: 258 (M+1). 99461.doc -47- 1295670

(b)7-(6-(4-(l-(4-氟苯基）乙基）六氫咐^井-1-基）嘧啶-4-基氧 基）喹啉。令得自上述步驟（a)之7-(6-氣基嘧啶-4-基氧基）喹 啉（0.045 g，0.18 mmol)與1-(-1 _(4_氟苯基）乙基）六氫吡畊、 實例 2(b)、（0.036 g，0.17 mmol)之 DMSO(0.5 mL)溶液於微 波爐合成器中以170°C加熱5min。令該反應混合物冷卻至室 溫並減壓蒸發。令殘渣經製備性HPLC[梯度：10-90% MeCN/(0.1%TFA之MeCN/H20)]生成TFA鹽之所需產物。溶 該鹽於DCM(25 mL)，並以飽和NaHC03(5 mL)溶液中和。 分開DCM層，經無水硫酸鈉乾燥並過濾。蒸發濾液並真空 乾燥殘渣，生成淡黃色油之標題化合物。MS (ESI，pos. ion.) m/z: 430 (M+l) 〇 實例29(b) 7-(6-(4-(l-(4-Fluorophenyl)ethyl)hexahydroindole^-yl)pyrimidin-4-yloxy)quinoline. 7-(6-Gasylpyrimidin-4-yloxy)quinoline (0.045 g, 0.18 mmol) and 1-(-1 _(4-fluorophenyl)ethyl) from the above step (a) Hexahydropyrazine, Example 2 (b), (0.036 g, 0.17 mmol) in DMSO (0.5 mL) was heated at 170 ° C for 5 min in a microwave oven synthesizer. The reaction mixture was allowed to cool to room temperature and evaporated under reduced pressure. The residue was subjected to preparative HPLC [gradient: 10-90% MeCN / (0.1% TFA of MeCN/H20)] to give the desired product of the TFA salt. The salt was dissolved in DCM (25 mL). The DCM layer was separated, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated and the residue was evaporated to dryness crystals MS (ESI, pos. ion.) m/z: 430 (M+l) 〇 Example 29

(&amp;)5-(6_氯基嘧啶-4-基氧基）異喹啉。令5-羥基異喹啉（0.431 g，2·97 mmol，Aldrich)與 4,6-二氯基 口密°定（0.442 g，2.97 mmol，Aldrich)於實例28(a)的條件下進行反應，生成淡黃 色非結晶固體之標題化合物。MS(ESI，pos· ion·) m/z: 25 8 (M+l)。 99461.doc -48- 1295670(&amp;) 5-(6-Chloropyrimidin-4-yloxy)isoquinoline. 5-Hydroxyisoquinoline (0.431 g, 2.97 mmol, Aldrich) was reacted with 4,6-dichloro-based (0.442 g, 2.97 mmol, Aldrich) under the conditions of Example 28 (a). The title compound is obtained as a pale yellow amorphous solid. MS (ESI, pos· ion·) m/z: 25 8 (M+l). 99461.doc -48- 1295670

(b)5-(6-(4-(l-(4-氟苯基）乙基）六氫《比啡-1-基）嘧啶基氧 基）異喹啉。令得自上述步驟（a)之5-(6-氯基嘧啶-4-基氧基） 異喹啉（0.2 13 g，0.83 mmol)與1-(1-(4-氟苯基）乙基）六氫吡 啩）、實例2(b)、（0.175 g，0·84 mmol)於實例28(b)之條件下(b) 5-(6-(4-(l-(4-Fluorophenyl)ethyl)hexahydro"picin-1-yl)pyrimidinyloxy)isoquinoline. 5-(6-Chloropyrimidin-4-yloxy)isoquinoline (0.213 g, 0.83 mmol) from 1-(1-(4-fluorophenyl)ethyl Hexahydropyridinium), Example 2 (b), (0.175 g, 0·84 mmol) under the conditions of Example 28(b)

進行反應，生成白色非結晶固體之標題化合物。MS(ESI，p〇s. ion·) m/z: 430 (M+1)。 實例30The reaction was carried out to give the title compound as a white white solid. MS (ESI, p〇s. ion·) m/z: 430 (M+1). Example 30

(a)8-(6-氣基嘴唆·4_基氧基）噎琳。令8-經基喧淋（0.435 g， 3·00 mmol，Sigma)與 4,6-二氣基嘴唆（0.449 g，3.01 mmol， Aldrich)於實例28(a)的條件下進行反應，生成淡黃色非結晶 固體之標題化合物。MS(ESI，pos· ion·) m/z: 258 (M+1)。(a) 8-(6-gas-based mouth 唆·4_yloxy) 噎琳. The reaction was carried out under the conditions of Example 28(a) by reacting 8-ionylphosphonate (0.435 g, 3.000 mmol, Sigma) with 4,6-di-gas oxime (0.449 g, 3.01 mmol, Aldrich). The title compound is a pale yellow amorphous solid. MS (ESI, pos· ion·) m/z: 258 (M+1).

(b)8-(6-(4-(l-(4-氟苯基）乙基）六氫吨畊-1-基）嘧啶-4-基氧 基）嗤啉。令得自上述步驟（a)之8-(6-氣基嘧啶-4-基氧基） 口奎淋（0.130 g，0·51 mmol)與1-(1-(4-氣苯基）乙基）六氫°比 99461.doc -49- 1295670 畊、實例2(b)、（0.105 g，0·50 mmol)於實例28(b)之條件下 進行反應，生成灰白色油之標題化合物。MS(ESI，pos. ion.) m/z: 430 (Μ+1) 〇 實例31(b) 8-(6-(4-(l-(4-Fluorophenyl)ethyl)hexahydroxanthan-1-yl)pyrimidin-4-yloxy)porphyrin. 8-(6-Gasylpyrimidin-4-yloxy) quinidine (0.130 g, 0·51 mmol) and 1-(1-(4-phenylphenyl) B from step (a) above The hexahydrogen ratio 99461.doc -49 - 1295670 cultivating, Example 2 (b), (0.105 g, 0. 50 mmol). MS (ESI, pos. ion.) m/z: 430 (Μ+1) 〇 Example 31

Cl (a)7-(6-氣基嘧淀-4-基氧基）異喹琳。令7-羥基異喹琳（0.2 86 g，1.97 mmol，Lancaster)與 4,6-二氣基喷咬（0.295 g，1.98 mmol，Aldrich)於實例28(a)的條件下進行反應，生成淡黃 色非結晶固體之標題化合物。MS(ESI，pos· ion·) m/z: 258 一 (Μ+1) 〇Cl (a) 7-(6-Gasylpyrazin-4-yloxy)isoquine. 7-Hydroxyisoquineline (0.286 g, 1.97 mmol, Lancaster) was reacted with 4,6-dialdehyde-based spray (0.295 g, 1.98 mmol, Aldrich) under the conditions of Example 28 (a) to give a light The title compound of the yellow amorphous solid. MS (ESI, pos· ion·) m/z: 258 one (Μ+1) 〇

Ο (b)7-(6-(4-(l-(4-氟苯基）乙基）六氫吼畊-1-基）嘧啶-4-基氧 基）異喹啉。令得自上述步驟（a)之7-(6-氯基嘧啶-4-基氧基） 異啥淋（0.038 g，0.15 mmol)與1-(1-(4-氟苯基）乙基）六氫。比 畊、實例 2(b)、（0.031 g，0.15 mmol)與二異丙基乙胺（0.050 g，0.29 mmol)之EtOH(0.75mL)混合物於微波爐合成器中以 165 °C加熱6 min。令反應混合物冷卻至室溫並減壓蒸發。 令殘渣經製備性HPLC[梯度：10-90% MeCN/(0.1%TFA之 MeCN/H20)]生成TFA鹽之所需產物。溶該鹽於 DCM(25mL)，並以飽和NaHC03(5mL)溶液中和。分開DCM 層，經無水硫酸鈉乾燥並過濾。蒸發濾液並真空乾燥殘渣， 99461.doc -50-(b) 7-(6-(4-(l-(4-Fluorophenyl)ethyl)hexahydroindol-1-yl)pyrimidin-4-yloxy)isoquinoline. 7-(6-Chloropyrimidin-4-yloxy)isoindole (0.038 g, 0.15 mmol) and 1-(1-(4-fluorophenyl)ethyl) from the above step (a) Hexahydrogen. A mixture of argon, Example 2 (b), (0.031 g, 0.15 mmol) and diisopropylethylamine (0.050 g, 0.29 mmol) in EtOH (0.75 mL) was heated at 165 °C for 6 min. The reaction mixture was cooled to room temperature and evaporated under reduced pressure. The residue was subjected to preparative HPLC [gradient: 10-90% MeCN / (0.1% TFA MeCN/H20)] to afford the desired product of the TFA salt. The salt was dissolved in DCM (25 mL) and neutralized with saturated NaHC03 (5 mL). The DCM layer was separated, dried over anhydrous sodium sulfate and filtered. Evaporate the filtrate and dry the residue in vacuo, 99461.doc -50-

1295670 生成灰白色油之標題化合物。MS(ESI，pos· ion·) m/z: 430 (M+l) 〇 實例321295670 The title compound was obtained as a white oil. MS (ESI, pos· ion·) m/z: 430 (M+l) 实例 Example 32

(&amp;)3-(6-氣基嘴淀-4-基氧基）異啥琳。令3-經基異喧琳（〇338 g，2.33 mmol，Aldrich)與 4,6-二氣基嘧啶（0.348 g，2.34 mmol，Aldrich)於實例28(a)的條件下進行反應，生成淡黃 色非結晶固體之標題化合物。MS(ESI，pos. ion.) m/z: 25 8 (M+l) 〇(&amp;) 3-(6-gas-based ylide-4-yloxy)isoindole. 3-glycosyl isoindene (〇338 g, 2.33 mmol, Aldrich) was reacted with 4,6-dioxapyrimidine (0.348 g, 2.34 mmol, Aldrich) under the conditions of Example 28 (a) to give a light The title compound of the yellow amorphous solid. MS (ESI, pos. ion.) m/z: 25 8 (M+l) 〇

(1〇3-(6-(4-(1-(4-氟苯基）乙基）六氫吼哨：-1_基）嘧咬-4_基氧 基）異喹啉。令得自上述步驟（a)之3-(6-氣基嘧啶-4-基氧基） 異喹啉（0.070 g，0.27 mmol)與1-(1-(4_氟苯基）乙基）六氫吡 畊、實例2(b)、（0.057 g，〇·27 mmol)於實例3 1(b)之條件下 進行反應，生成白色非結晶固體之標題化合物。MS(ESI，p〇s ion·) m/z: 430 (M+l) 〇 實例33(1〇3-(6-(4-(1-(4-fluorophenyl)ethyl)hexahydropyrene:-1-1-yl)pyrimidine-4_yloxy)isoquinoline. 3-(6-Azinopyrimidin-4-yloxy)isoquinoline (0.070 g, 0.27 mmol) of the above step (a) and 1-(1-(4-fluorophenyl)ethyl)hexahydropyridyl Cultivating, Example 2 (b), (0.057 g, 〇·27 mmol) was carried out under the conditions of Example 3 1 (b) to give the title compound as a white white solid. MS (ESI, p〇s ion·) m /z: 430 (M+l) 〇Example 33

(a)4·氟基·6-(4-(1-(4-氟苯基）乙基）六氫n比啡-1-基）嘧啶。將 99461.doc -51 - 1295670 碳酸鉋（2.3 g，7.2 mmol)於0°C 攪拌加入 l-[(lS，lR)·l-(4_氟 苯基）-乙基]-六氫σ比畊、實例2(b)、（0·50g，2.4mmol)與4,6-二氣基嘧啶（0.28 mL，2.4 mmo卜 ABCR)之DMF(8 mL)混合 物。令該反應混合物於0°C攪拌20 min，經H2O(20 mL)稀 釋，並經DCM(2x40 mL)萃取。令合併之有機萃取物經H20(2 x40 mL)洗，經Na2S04乾燥與過濾。蒸發濃縮濾液並令殘渣 真空乾燥，產生標題化合物。MS(ESI，pos_ ion·) m/z: 305 (M+l)。(a) 4-fluoro-6-(4-(1-(4-fluorophenyl)ethyl)hexahydron-p-ment-1-yl)pyrimidine. Add 99461.doc -51 - 1295670 carbonate planer (2.3 g, 7.2 mmol) at 0 °C to add 1-[(lS,lR)·l-(4-fluorophenyl)-ethyl]-hexahydro-sigma ratio A mixture of cultivating, Example 2 (b), (0.50 g, 2.4 mmol) and 4,6-dioxapyrimidine (0.28 mL, 2.4 mmo ABCR) in DMF (8 mL). The reaction mixture was stirred at EtOAc (EtOAc) EtOAc (EtOAc) The combined organic extracts were washed with H20 (2×40 mL) and dried over Na 2 EtOAc. The filtrate was concentrated by evaporation. MS (ESI, pos_ ion·) m/z: 305 (M+l).

(b)2-(6-(4-(l-(4-氟苯基）乙基）六氫吼畊-1-基）嘧啶-4_基氧 基）喹啉。將 95%氫化鈉（0.027 g，1· 13 mmol，Aldrich)加入 得自上述步驟（a)之4 -氣基- 6- (4-(1-(4 -氣苯基）乙基）六氣σ比 畊-1·基）嘧啶（0.178 g，0.59 mmol)與喹啉-2-醇（0.085 g，0.59 mmol，Aldrich)之DMS0(2.0 mL)溶液。令該混合物於室溫 攪拌15 min，然後於微波爐合成器中以170QC加熱5 min。令 反應混合物冷卻至室溫並減壓蒸發。令殘渣經製備性 HPLC[梯度：10-90% MeCN/(0.1%TFA之MeCN/H20)]純化而 生成TFA鹽之所需產物。溶該鹽於DCM(25mL)，並以飽和 NaHC〇3(5 mL)溶液中和。分開DCM層，經無水硫酸鈉乾燥 並過濾。蒸發濾液並真空乾燥殘渣，生成灰白色油之標題 化合物。MS(ESI，pos· ion.) m/z: 430 (M+1)。 99461.doc -52- 1295670 實例34(b) 2-(6-(4-(l-(4-Fluorophenyl)ethyl)hexahydroindol-1-yl)pyrimidin-4-yloxy)quinoline. 95% sodium hydride (0.027 g, 1.33 mmol, Aldrich) was added to the 4-(4-(4-(4-phenylphenyl)ethyl) 6 gas from step (a) above. A solution of σ-ratio-1·yl)pyrimidine (0.178 g, 0.59 mmol) and quinoline-2-ol (0.085 g, 0.59 mmol, Aldrich) in EtOAc (2.0 mL). The mixture was stirred at room temperature for 15 min and then heated at 170QC for 5 min in a microwave synthesizer. The reaction mixture was allowed to cool to room temperature and evaporated under reduced pressure. The residue was purified by preparative HPLC [gradient: 10-90% MeCN / (0.1% TFA MeCN/H20)] to give the desired product of the TFA salt. The salt was dissolved in DCM (25 mL) and was taken to sat. The DCM layer was separated, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated and the residue was dried <RTI ID=0.0> MS (ESI, pos. ion.) m/z: 430 (M+1). 99461.doc -52- 1295670 Example 34

(a)4-(6-氣基喊咬-4·基氧基）啥琳。令4-經基噎琳（0.435 g， 2 ·99 mmo卜 Aldrich)、4,6-二氯基癌唆（0.453 g，3.04 mmol， Aldrich)與 MP-碳酸鹽樹月旨（0.369 g，2.67 mmol，2.73 mmol/g，Argonaut)之ΝΜΡ(2·5 mL)溶液的混合物於室溫授 拌2h，然後於微波爐合成器中以100°C加熱5 min。令反應 混合物冷卻至室溫並過濾去除樹脂。令濾塊經甲醇（10 mL) 洗，並將合併之濾液減壓濃縮。令該紅棕色殘渣經矽膠管 柱色析（梯度：0-5% MeOH/DCM)純化，提供淡黃色非結晶固 體之標題化合物。MS(ESI，pos· ion·) m/z: 25 8 (M+1)。(a) 4-(6-gas-based shunting -4 yloxy) 啥琳. 4- 噎 基噎琳 (0.435 g, 2 · 99 mmo Bu Aldrich), 4,6-dichlorocarcinoma (0.453 g, 3.04 mmol, Aldrich) and MP-carbonate tree (0.369 g, 2.67) A mixture of mmol, 2.73 mmol/g, Argonaut) (2.5 mL) was stirred at room temperature for 2 h and then heated at 100 ° C for 5 min in a microwave synthesizer. The reaction mixture was allowed to cool to room temperature and filtered to remove the resin. The filter was washed with methanol (10 mL) and the combined filtrate was evaporated. The reddish brown residue was purified by EtOAc (EtOAc:EtOAc) MS (ESI, pos· ion·) m/z: 25 8 (M+1).

(b)4-(6-(4-(l-(4-氟苯基）乙基）六氫啦畊-1-基）嘧啶_4-基氧 基）喹啉。令得自上述步驟（a)之4-(6-氣基嘧啶-4-基氧基）喹 啉（0.060 g，0.23 mmol)與1-(1_(4-氟苯基）乙基）六氫吡畊、 實例2(b)、（0.049 g，0.24 mmol)於實例31(b)之條件下進行 反應，生成灰白色油之標題化合物。MS (ESI，pos. ion.) m/z: 430 (M+1)。 實例35(b) 4-(6-(4-(l-(4-Fluorophenyl)ethyl)hexahydroylidene-1-yl)pyrimidine-4-yloxy)quinoline. 4-(6-Gasylpyrimidin-4-yloxy)quinoline (0.060 g, 0.23 mmol) and 1-(1-(4-fluorophenyl)ethyl)hexahydrochloride obtained from the above step (a) Pyridine, Example 2 (b), (0.049 g, 0.24 mmol). MS (ESI, pos. ion.) m/z: 430 (M+1). Example 35

99461.doc - 53 - 1295670 (a)2,3_二氫苯并[b][l，4]二嘮畊-6·基乙酸鹽。令1_(2,3-二氫 苯并[匕][1，4]二4_-6-基）乙酮（1.548 §，8.69 111111〇1，八1(114(：11) 與3 -氣基-過氧化爷酸（4.35 g，19.41 mmol，77%重量， Aldrich)之DCM(5 5 mL)溶液於油浴中加熱至65°C達17.5h。 令該反應混合物冷卻至室溫並以DCM(150 mL)與水（50 mL) 稀釋。分開DCM層，以飽和NaHC03(100 mL)與鹽液（25 mL) 洗，經無水硫酸鈉乾燥並過濾。蒸發濾液並令殘渣真空乾 燥，生成非結晶固體之標題化合物。MS(ESI，pos. ion.) m/z: 195 (M+l) 〇99461.doc - 53 - 1295670 (a) 2,3_Dihydrobenzo[b][l,4]dioxin-6-yl acetate. Let 1_(2,3-dihydrobenzo[匕][1,4]di-4-_-yl)ethanone (1.548 §, 8.69 111111〇1, 八1(114(:11) and 3-air base - a solution of peroxidic acid (4.35 g, 19.41 mmol, 77% by weight, Aldrich) in DCM (5 5 mL) was heated in an oil bath to 65 ° C for 17.5 h. The reaction mixture was cooled to room temperature and DCM (150 mL) was diluted with water (50 mL). The DCM layer was separated, washed with saturated NaHC03 (100 mL) and brine (25 mL), dried over anhydrous sodium sulfate and filtered and evaporated. The title compound of the crystalline solid. MS (ESI, pos. ion.) m/z: 195 (M+l) 〇

(b)2,3-二氫苯并[b][l，4]二嘮畊-6-醇。令得自上述步驟（a) 之2,3-二氫苯并[b][l，4]二噚畊-6-基乙酸鹽（1.65 g，10.84 mmol，Aldrich)之 MeOH(80 mL)溶液與 2.5N NaOH( 120 mL) 一起於室溫攪拌21h。減壓蒸發MeOH，並以EtOAc(200 mL) 稀釋殘潰。分開EtOAc層，經無水硫酸納乾燥並過渡。蒸發 濾液並令殘渣真空乾燥，生成紅棕色固體。將固體懸浮於 MeOH(10 mL)並過濾。令濾塊真空乾燥，生成非結晶固體 之標題化合物。MS(ESI，pos· ion.) m/z: 153 (M+1) 〇(b) 2,3-Dihydrobenzo[b][l,4]dioxin-6-ol. a solution of 2,3-dihydrobenzo[b][l,4]dioxin-6-yl acetate (1.65 g, 10.84 mmol, Aldrich) in MeOH (80 mL) from step (a) Stir at room temperature for 21 h with 2.5 N NaOH (120 mL). The MeOH was evaporated under reduced pressure and diluted with EtOAc (EtOAc) The EtOAc layer was separated, dried over anhydrous sodium sulfate and evaporated. The filtrate was evaporated and the residue was dried in vacuo to give a red brown solid. The solid was suspended in MeOH (10 mL) and filtered. The filter cake was dried under vacuum to give the title compound as a crystal solid. MS (ESI, pos. ion.) m/z: 153 (M+1) 〇

(c)4-氯基-6-(2,3-二氫苯并[b][l，4]二噚畊-6-基氧基）嘧啶。 令得自上述步驟（b)之2,3-二氫苯并[b][l，4]二呤畊-6-醇 99461.doc -54- 1295670 (0.500 g，3·29 mmol)、4,6·二氣基嘧啶（〇·4ΐ7 g，2·80 mmo卜 Aldrich)與 MP-碳酸鹽樹脂（1·41 g，4.09 mmo 卜 2.9 mmol/g , Argonaut)之ΝΜΡ(3·0 mL)的混合物於室溫攪拌2h，然後於 微波爐合成器中以110°C加熱6 min。令反應混合物冷卻至 室溫並過濾去除樹脂。令濾塊經甲醇（1 〇 mL)洗，並減壓蒸 發濾液。令該紅棕色殘渣經矽膠管柱色析（梯度：0_5〇/〇 MeOH/DCM)純化，提供淡黃色非結晶固體之標題化合物。 MS(ESI，pos· ion·) m/z: 265 (M+1) 〇(c) 4-Chloro-6-(2,3-dihydrobenzo[b][l,4]dioxan-6-yloxy)pyrimidine. 2,3-Dihydrobenzo[b][l,4]diterpene-6-ol 99461.doc -54- 1295670 (0.500 g, 3.29 mmol), 4 obtained from the above step (b) ,6·Dimethylpyrimidine (〇·4ΐ7 g, 2·80 mmo Bu Aldrich) and MP-carbonate resin (1·41 g, 4.09 mmo 2.9 mmol/g, Argonaut) (ΝΜΡ·3 mL) The mixture was stirred at room temperature for 2 h and then heated at 110 ° C for 6 min in a microwave oven synthesizer. The reaction mixture was allowed to cool to room temperature and filtered to remove the resin. The filter was washed with methanol (1 〇 mL) and the filtrate was evaporated under reduced pressure. The reddish brown residue was purified by EtOAc (EtOAc:EtOAc:EtOAc MS (ESI, pos· ion·) m/z: 265 (M+1) 〇

(d)4-(2,3-二氫苯并[b][l，4]二嘮畔-6-基氧基）-6-(4兴卜(4-氟 笨基）乙基）六氫咐^井-1-基）喊唆。令得自上述步驟（c)之4_氣 基-6-(2,3-二氫苯并[b][l，4]二喝畊_6_基氧基）嘧啶（〇 156 8,0.59 111111〇1)與1-(1-(4-氟苯基）乙基）六氫响畊、實例2(13)、 (0.123g’ 0.59mmol)於實例31(b)之條件下進行反應，生成 灰白色油之標題化合物。MS(ESI，p〇s i〇n ) m/z· 437 (M+1) 〇 實例36(d) 4-(2,3-Dihydrobenzo[b][l,4]diindol-6-yloxy)-6-(4 (b)-(4-fluorophenyl)ethyl) Hydrogen 咐^ well-1-base) shouted. 4_ gas-based-6-(2,3-dihydrobenzo[b][l,4]di-terminated _6-yloxy)pyrimidine (〇156 8,0.59) obtained from the above step (c) 111111〇1) reacted with 1-(1-(4-fluorophenyl)ethyl)hexahydropyrazine, Example 2 (13), (0.123 g '0.59 mmol) under the conditions of Example 31 (b), The title compound was obtained as a white oil. MS (ESI, p〇s i〇n ) m/z· 437 (M+1) 〇 Example 36

(a)3-氧基-3,4-二氫·2H_苯并[b][1，4]二嘮啡·6_基乙酸鹽。令 6-乙醯基-2Η-苯并[b][1，4]二哼畊 _3(4Η)^(ι ΐ33 §% 99461.doc -55- 1295670 mmol，Aldrich)於實例35(a)之條件下經3-氯基過氧化苄酸 (3.15 g，14.06 mmol，77%重量，Aldrich)處理，生成非結 晶固體之標題化合物。MS(ESI，pos· ion·) m/z: 208 (M+1)。(a) 3-oxy-3,4-dihydro-2H-benzo[b][1,4]di- morphinyl-6-yl acetate. Let 6-ethylindolyl-2Η-benzo[b][1,4]dioxin _3(4Η)^(ι ΐ33 §% 99461.doc -55- 1295670 mmol, Aldrich) in Example 35(a) Treatment with 3-chloroperoxybenzoic acid (3.15 g, 14.06 mmol, 77% by weight, Aldrich) afforded the title compound as crystals. MS (ESI, pos· ion·) m/z: 208 (M+1).

(b)6-羥基-2H-苯并[b][l，4]二嘮畊-3(4H)-酮。令得自上述步 驟（a)之3-酮基_3,4_二氫-2H-苯并[b][l，4]二噚畊-6-基乙酸(b) 6-Hydroxy-2H-benzo[b][l,4]dioxin-3(4H)-one. 3-keto- 3,4-dihydro-2H-benzo[b][l,4]diterpene-6-yl acetic acid obtained from the above step (a)

鹽（1.21 g，5.84 mmo卜 Aldrich)之MeOH(80 mL)於實例 35(b) 之條件下與2.5NNaOH(120 mL)進行反應，生成非結晶固體 之標題化合物。MS(ESI，pos· ion·) m/z: 166 (M+1)。The salt (1.21 g, 5.84 mmol, Aldrich) in MeOH (EtOAc) (EtOAc) MS (ESI, pos· ion·) m/z: 166 (M+1).

(c)6-(6-氯基嘧啶-4-基氧基）-2H-苯并[b][l，4]二噚畊-3(4H)-酮。令得自上述步驟（b)之6-羥基-2H-苯并[b][l，4]二嘮畊 -3(4H)-酮（0.325 g，1.97 mmol)與 4,6-二氣基喊唆（0.264 g， 1.77 mmol，Aldrich)於實例35(c)之條件下進行反應，生成 淡黃色非結晶固體之標題化合物。MS(ESI，pos· ion·) m/z: 278 (M+l)。(c) 6-(6-Chloropyrimidin-4-yloxy)-2H-benzo[b][l,4]dioxin-3(4H)-one. 6-Hydroxy-2H-benzo[b][l,4]diterpene-3(4H)-one (0.325 g, 1.97 mmol) and 4,6-diyl group obtained from the above step (b) The title compound was obtained as a pale yellow amorphous solid. MS (ESI, pos. ion.) m/z: 278 (M+l).

99461.doc -56- d 1295670 基）-2H-苯并[b][i，4]二啰畊-3(4H)-酮。令得自上述步驟（c) 之6_(6-氣基嘧啶·‘基氧基）-2H苯并二呤畊-3(411)-_ (0·085 g，〇·3ΐ瓜^^^與^(卜^·氟苯基）乙基）六氫0比畊）、 實例2(b)、（〇·〇67 g，0.32 mmol)於實例31(b)之條件下進行 反應’生成灰白色油之標題化合物。MS(ESI，pos· ion.) m/z: 450 (M+l) 〇 實例3799461.doc -56- d 1295670 yl)-2H-benzo[b][i,4]dioxin-3(4H)-one. 6_(6-Alkylpyrimidinyl-yloxy)-2H benzoindole-3(411)-_ (0·085 g, 〇·3ΐ瓜^^^ with the above step (c) ^(Bu fluorophenyl)ethyl)hexahydro 0 to plough), Example 2 (b), (〇·〇67 g, 0.32 mmol) was reacted under the conditions of Example 31 (b) to produce an off-white oil The title compound. MS (ESI, pos. ion.) m/z: 450 (M+l) 实例 Example 37

(a)5-(6-氣基嘴咬·4·基氧基）啥琳。令5_經基哇琳（〇·292 g， 2·01 mmol，Aldrich)與 4,6-二氣基嘧啶（0.3 g，2.01 mmol， Aldrich)於實例34(a)之條件下進行反應，生成淡黃色非結晶 固體之標題化合物。MS(ESI，pos. ion.) m/z: 258 (M+1)。(a) 5-(6-gas base bite · 4 · oxy) 啥 Lin. 5_ via Kivalin (〇·292 g, 2·01 mmol, Aldrich) and 4,6-dioxapyrimidine (0.3 g, 2.01 mmol, Aldrich) were reacted under the conditions of Example 34 (a), The title compound was obtained as a pale yellow amorphous solid. MS (ESI, pos. ion.) m/z: 258 (M+1).

(b )5-(6-(4 _(1_ (4 苯基）乙基）六氫α比哨•基）痛咬-4 _基氧 基）喹啉。令得自上述步驟（a)之5-(6-氯基嘧啶-4-基氧基）喹 啉（0.130 g，0.51 mmol)、1-(1·(4_氟苯基）乙基）六氫吡畊、 實例 2(b)、（0.107 g，0.51 mmol)與 PS-DIEA樹脂（0.40 g，1.49 mmol，3·72 mmol/g，Argonaut)之EtOH(4.0 mL)的混合物於 室溫攪拌2h，然後於微波爐合成器中以160°C加熱6 min。 令反應混合物冷卻至室溫並過濾去除樹脂。令樹脂經甲醇 99461.doc -57- 1295670 (10 mL)洗，並減壓蒸發合併之濾液。溶膠狀殘渣於 MeOH(2.5 mL)並藉製備性 HPLC[梯度：10-90% MeCN/(0.1%TFA之MeCN/H20)]生成TFA鹽之所需產物。溶 該鹽於DCM(25 mL)，並以飽和NaHC03(5 mL)中和。分開 DCM層，經無水硫酸鈉乾燥並過濾。蒸發濾液並真空乾燥 殘渣，生成灰白色油之標題化合物。MS(ESI，pos. ion.) m/z: 430 (M+l)。 實例38(b) 5-(6-(4 _(1_(4 phenyl)ethyl)hexahydro-α) whistyl)-bite-4 _yloxy)quinoline. 5-(6-Chloropyrimidin-4-yloxy)quinoline (0.130 g, 0.51 mmol), 1-(1·(4-fluorophenyl)ethyl)hexa(6) Mixture of hydrogen pyridin, Example 2 (b), (0.107 g, 0.51 mmol) and PS-DIEA resin (0.40 g, 1.49 mmol, 3.72 mmol/g, Argonaut) in EtOH (4.0 mL). 2h, then heated at 160 ° C for 6 min in a microwave synthesizer. The reaction mixture was allowed to cool to room temperature and filtered to remove the resin. The resin was washed with methanol 99461.doc -57 - 1295670 (10 mL), and the combined filtrate was evaporated. The sol residue was taken up in MeOH (2.5 mL The salt was dissolved in DCM (25 mL). The DCM layer was separated, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated and the residue was evaporated mjjjjjjjj MS (ESI, pos. ion.) m/z: 430 (M+l). Example 38

(a)6-(6-氣基嘧啶-4-基氧基）異喹啉。令6-羥基異喹啉（0.294 g，2·03 mmol，J&amp;W Pharma Lab)與 4,6-二氯基嘴咬（0.302 g，2.03 mmol，Aldrich)於實例34(a)的條件下進行反應，生 成淡黃色非結晶固體之標題化合物。MS(ESI，pos. ion.) m/z·· 258 (M+l)。(a) 6-(6-Gasylpyrimidin-4-yloxy)isoquinoline. 6-Hydroxyisoquinoline (0.294 g, 2·03 mmol, J&amp;W Pharma Lab) and 4,6-dichloro-based mouth bit (0.302 g, 2.03 mmol, Aldrich) under the conditions of Example 34 (a) The reaction was carried out to give the title compound as a pale yellow solid. MS (ESI, pos. ion.) m/z·· 258 (M+l).

(b)6-(6-(4_(l-(4·氣苯基）乙基）六鼠吼^1井-1-基）13密唆-4 -基氧 基）異喹啉。令得自上述步驟（a)之6-(6-氣基嘧啶-4-基氧基） 異喹啉（0.136 g，0.53 mmol)與1-(1-(4-氟苯基）乙基）六氫吡 畊、實例2(b)、（0.112 g，0.54 mmol)於實例37(b)之條件下 進行反應。令粗產物經製備性HPLC[梯度=10-90% 99461.doc -58- 1295670(b) 6-(6-(4-(l-(4.Phenylphenyl)ethyl)hexahydropyran-1-yl-1-yl)13-mercapto-4-yloxy)isoquinoline. 6-(6-Gasylpyrimidin-4-yloxy)isoquinoline (0.136 g, 0.53 mmol) from 1-(1-(4-fluorophenyl)ethyl) Hexahydropyrazine, Example 2 (b), (0.112 g, 0.54 mmol) was reacted under the conditions of Example 37 (b). The crude product was subjected to preparative HPLC [gradient = 10-90% 99461.doc -58-1295670

MeCN/(0.1% TFA) /Η2Ο(0·1% TFA)]，生成灰白色油之標題 化合物。MS(ESI，pos· ion·) m/z: 430 (M+1)。 實例39MeCN / (0.1% TFA) / Η 2 Ο (0·1% TFA)], which produced the title compound of the off-white oil. MS (ESI, pos· ion·) m/z: 430 (M+1). Example 39

(a)6-(6-氣基嘧啶-4-基氧基）-3,4-二氫-2H-苯并[b][l，4]噚畊 令 3,4-二氫-2H-苯并[b][l，4]噚畊-6_ 醇（0·152 g，1·01 mmol，Matrix)與 4，6-二氣基喊唆（0.15 g，1.01 mmol，Aldrich) 於實例34(a)的條件下進行反應，生成淡黃色非結晶固體之 標題化合物。MS(ESI，pos· ion·) m/z: 264 (M+1) 〇(a) 6-(6-Azinopyrimidin-4-yloxy)-3,4-dihydro-2H-benzo[b][l,4]indole 3,4-dihydro-2H- Benzo[b][l,4]indole-6-alcohol (0·152 g,1·01 mmol, Matrix) and 4,6-di-gas group (0.15 g, 1.01 mmol, Aldrich) in Example 34 The reaction is carried out under the conditions of (a) to give the title compound as a pale yellow solid. MS (ESI, pos· ion·) m/z: 264 (M+1) 〇

(b)6-(6-(4-(l-(4 -氟苯基）乙基）六氫β比畊-1_基）嘴唆_4_基氧 基）-3,4-二氫-2H_苯并[b][l，4]嘮畊。令得自上述步驟（a)之 6-(6-氣基嘧啶_4_基氧基）-3,4-二氫-2H-笨并[b][l，4]吟呼 (0.043 g，〇·17 mmol)與1-(1-(4-氟苯基）乙基）六氫吼畔 '實 例2(b)、（0.040 g，0.19 mmol)於實例31(b)之條件下進行反 應’生成非結晶之白色固體之標題化合物。p〇s ion.) m/z: 436 (M+1) 〇 實例40(b) 6-(6-(4-(l-(4-fluorophenyl)ethyl)hexahydro-β ratio tillage-1_yl) 唆4_yloxy)-3,4-dihydro -2H_Benzo[b][l,4] tillage. 6-(6-Amphetylpyrimidin-4-yloxy)-3,4-dihydro-2H-abido[b][l,4]吟 (0.043 g, obtained from the above step (a) 〇·17 mmol) and 1-(1-(4-fluorophenyl)ethyl)hexahydropurine 'Example 2 (b), (0.040 g, 0.19 mmol) were reacted under the conditions of Example 31 (b) 'The title compound is formed as a non-crystalline white solid. P〇s ion.) m/z: 436 (M+1) 〇 Example 40

99461.doc -59- 1295670 (a)4_(6-氯基嘧啶-4-基氧基）異喹啉。令異喹琳-4-醇（0.436 g，3.00 mmol，Monomer Chem)與 4,6-二氣基嘴 σ定（〇·449 g， 3 ·01 mmol，Aldrich)於實例34(a)的條件下進行反應，生成 淡黃色非結晶固體之標題化合物。MS(ESI，pos· i〇n.) m/z: 258 (M+l) 〇99461.doc -59- 1295670 (a) 4-(6-Chloropyrimidin-4-yloxy)isoquinoline. The conditions of Example 34(a) for isoquinolin-4-ol (0.436 g, 3.00 mmol, Monomer Chem) and 4,6-diyl group sigma (〇·449 g, 3 · 01 mmol, Aldrich) The reaction was carried out to give the title compound as a pale yellow amorphous solid. MS (ESI, pos· i〇n.) m/z: 258 (M+l) 〇

(b)4-(6_(4_(l-(4·氟苯基）乙基）六氫α比畊-1-基）嘴唆-4-基氧 基）異啥琳。令得自上述步驟（a)之4-(6-氣基，唆-4-基氧基） 異喹啉（0.162 g，0.63 mmol)與1-(1-(4-氟苯基）乙基）六氫吡 畊、實例2(b)、（0.135 g，0.65 mmol)於實例3 1(b)之條件下 進行反應，生成非結晶白色固體之標題化合物。MS(ESI，P〇s ion·) m/z: 430 (M+1)。 實例41(b) 4-(6-(4_(l-(4.Fluorophenyl)ethyl)hexahydro-α than cultivating-1-yl) oxime-4-yloxy)isoindole. 4-(6-Gas, indol-4-yloxy)isoquinoline (0.162 g, 0.63 mmol) from 1-(1-(4-fluorophenyl)ethyl The hexahydropyrazine, Example 2 (b), (0.135 g, 0.65 mmol) was taken to give the title compound as a white solid. MS (ESI, P〇s ion·) m/z: 430 (M+1). Example 41

(a)2,3_ 二氫苯并[b][l，4]二 $ 畊 _5_ 醇。令苯 _i，2,3_ 三醇（4·39 g’ 34.81 mmo卜 Aldrich)、l，2-二溴乙烷（1 mL，11.6 mmo卜 Aldrich)與碳酸鉀（ι·6〇 g，1158 mmol，Alddch)之 2_ 丁酮 (300 mL ’ Aldrich)混合物於油浴中攪拌廻流加熱達 18.5h。令該反應混合物冷卻至室溫並以DCM(1〇〇 mL)與水 (50 mL)稀釋。分開DCM層，以1〇% Na2s2〇3(5〇 mL)與鹽液 99461.doc -60- 1295670 ( )洗免無水硫酸納乾燥、過遽並蒸發。令殘潰經 矽膠官柱色析（梯度：0-5% MeOH/DCM)純化，生成非結晶固 體之‘通化合物。MS(ESI，pos. ion·) m/z: 153 (M+1)。(a) 2,3_Dihydrobenzo[b][l,4] two $ till _5_ alcohol. Benzene_i,2,3_ triol (4·39 g' 34.81 mmo Bu Aldrich), l,2-dibromoethane (1 mL, 11.6 mmo Bu Aldrich) and potassium carbonate (ι·6〇g, 1158 A mixture of 2-butanone (300 mL 'Aldrich) of mmol, Alddch) was stirred in an oil bath for up to 18.5 h. The reaction mixture was cooled to room temperature and diluted with DCM (1 mL) and water (50 mL). The DCM layer was separated, washed with 1% Na2s2 〇3 (5 〇 mL) and salt liquid 99461.doc -60 - 1295670 ( ), dried over anhydrous sodium sulfate, dried and evaporated. The residue was purified by chromatography on a silica gel column (gradient: 0-5% MeOH/DCM) to yield a compound of the amorphous solid. MS (ESI, pos. ion·) m/z: 153 (M+1).

(b)4-氯基-6-(2,3-二氫苯并二哼畊-5-基氧基）嘧啶。 令得自上述步驟⑷之2,3_二氫苯并[b][1，4]二嘮畊-5-醇 (0·247 g’ 1·62 mm〇i)與4,6_二氣基嘧啶（0.232 g，1.56 mmol ’ Aldrich)於實例34(a)的條件下進行反應，生成淡黃 色非結晶固體之標題化合物。MS(ESI，pos. ion.) m/z: 265 (M+1) °(b) 4-Chloro-6-(2,3-dihydrobenzoindole-5-yloxy)pyrimidine. 2,3_Dihydrobenzo[b][1,4]dioxin-5-ol (0·247 g'1·62 mm〇i) and 4,6_two gas obtained from the above step (4) The cytosine (0.232 g, 1.56 mmol &lt;RTI ID=0.0&gt; MS (ESI, pos. ion.) m/z: 265 (M+1) °

N^NN^N

(〇4-(2,3_二氫苯并[13][1，4]二嘮畊-5-基氧基）-6_(4-(1-(4_氟 本基）乙基）·六氫咐^井-1·基）喊唆。令得自上述（b)之4-氣基 •6-(2,3-二氫苯并[b][l，4]二巧_-5-基氧基 P密唆（0.234 g， 〇·88 mmol)與1-(1-(4-氟苯基）乙基）六氫吼畊、實例2(b)、 (〇.185g，0·89 mmol)於實例31(b)之條件下進行反應，生成 非結晶白色固體之標題化合物。MS(ESI，pos. ion·) m/z: 437 (M+1) ° 實例42 99461.doc -61 - 1295670 ，〇，(〇4-(2,3-dihydrobenzo[13][1,4]dioxin-5-yloxy)-6-(4-(1-(4-fluorophenyl)ethyl)· Hexahydro 咐^ well-1·base) shouting. Order 4-(6,3-dihydrobenzo[b][l,4] bis- _-5 from (b) above - yloxy P crypt (0.234 g, 〇·88 mmol) and 1-(1-(4-fluorophenyl)ethyl)hexahydroindole, Example 2 (b), (〇.185g, 0· 89 mmol) The title compound was obtained as crystals m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m 61 - 1295670, hey,

Cl ⑷6-(6-氯基喊啶-4-基氧基）啥啉。令6_經基喧琳（ο· §， 2_98 mm〇1’ AMdch)與 4,6·二氣基嘧咬（〇 445 g，2 % 咖〇1 ,Cl (4) 6-(6-Chloro-cyano-4-yloxy)porphyrin. Order 6_ by Keelin (ο· §, 2_98 mm〇1’ AMdch) and 4,6· di-nitropyrimidine (〇 445 g, 2 % curry 1 ,

Aidrich)於實例28(a)的條件下進行反應，生成淡冑色非結晶 固體之標題化合物。MS(ESI，p〇s&gt;…叫m/z: 258 (M+1pAidrich) was reacted under the conditions of Example 28 (a) to give the title compound as a pale, pale solid. MS (ESI, p〇s &gt;...called m/z: 258 (M+1p

(b)6-(6-(4-(l-(4-氟苯基）乙基）六氫α比畊-^基）嘧啶_4•基氧 基）喹啉。令得自上述步驟（a)之6-(6-氣基嘧啶_4_基氧基）喹 啉（0.135 g，0.52 mmol)與1-(1-(4-氟苯基）乙基）六氫吡畊、 實例2(b)、（0.109 g，0.52 mmol)於實例28(b)之條件下進行 反應，生成白色非結晶固體之標題化合物© MS (ESI，pos. ion·) m/z: 430 (M+1)。(b) 6-(6-(4-(l-(4-Fluorophenyl)ethyl)hexahydro-α than cultivating-yl)pyrimidin-4-yloxy)quinoline. 6-(6-Gasylpyrimidin-4-yloxy)quinoline (0.135 g, 0.52 mmol) from 1-(1-(4-fluorophenyl)ethyl) Hydrogen pyridinium, Example 2 (b), (0.109 g, 0.52 mmol) was obtained from the title compound of Example 28 (b) to give the title compound: MS (ESI, pos. ion·) m/z : 430 (M+1).

實例43Example 43

(a)5-(6-氣基嘧啶_4-基氧基）-3,4-二氫異喹啉-1(2H)-酮。令 5-羥基-3,4-二氫異喹啉-1(2H)-酮（0.274 g，1.68 mmol， Chempacific)與 4,6-二氣基喊淀（0.251 g，1.69 mmol ’ Aldrich) 於實例34(a)的條件下進行反應，生成淡黃色非結晶固體之 標題化合物。MS(ESI，pos. ion.) m/z: 276 (M+1)。 99461.doc -62- 1295670(a) 5-(6-Carbopyrimidin-4-yloxy)-3,4-dihydroisoquinolin-1(2H)-one. 5-hydroxy-3,4-dihydroisoquinolin-1(2H)-one (0.274 g, 1.68 mmol, Chempacific) and 4,6-di-gas group (0.251 g, 1.69 mmol 'Aldrich) The reaction was carried out under the conditions of Example 34 (a) to give the title compound as a pale yellow solid. MS (ESI, pos. ion.) m/z: 276 (M+1). 99461.doc -62- 1295670

(b)5-(6-(4-(l-(4-氟苯基）乙基）六氫处畊-1-基）嘧啶-4-基氧 基）-3,4-二氫異喹啉-1(2H)-酮。令得自上述步驟（a)之5-(6· 氯基嘧啶·4-基氧基）-3,4-二氫異喹啉-1(2H)-酮（0.214 g， 0.78 mmol)與1-(1·(4-氟苯基）乙基）六氫吼畊、實例2(b)、 (0.162 g，0.78 mmol)於實例37(b)之條件下進行反應，生成 灰白色油之標題化合物。MS(ESI，pos. ion·) m/z: 448 (M+l) 〇 實例44 OH 沾。 Η (a)4-羥基-1H_苯并[d]咪唑-2(3H)-酮。將羰基二咪唑（1·62 g，10 mmol，Aldrich)加入 2，3-二胺基-盼（1.24 g，10 mmol， Aldrich)之THF(25 mL)懸浮液。令該反應混合物於室溫攪拌 16h，並真空蒸發。令油狀殘渣懸浮於MeOH並過濾固體沈 澱物。令濾塊經真空乾燥，生成標題化合物。MS(ESI，pos. ion·) m/z: 15 1 (Μ+1) 〇(b) 5-(6-(4-(l-(4-Fluorophenyl)ethyl)hexahydroindol-1-yl)pyrimidin-4-yloxy)-3,4-dihydroisoquine Porphyrin-1(2H)-one. 5-(6·Chloropyrimidin-4-yloxy)-3,4-dihydroisoquinolin-1(2H)-one (0.214 g, 0.78 mmol) obtained from the above step (a) -(1.(4-Fluorophenyl)ethyl)hexahydroindole, Example 2(b), (0.162 g, 0.78 mmol). . MS (ESI, pos. ion·) m/z: 448 (M+l) 〇 Example 44 OH. Η (a) 4-Hydroxy-1H_benzo[d]imidazole-2(3H)-one. A carbonyl diimidazole (1·62 g, 10 mmol, Aldrich) was added to a suspension of 2,3-diamino-pan (1.24 g, 10 mmol, Aldrich) in THF (25 mL). The reaction mixture was stirred at room temperature for 16 h and evaporated in vacuo. The oily residue was suspended in MeOH and the solid precipitate was filtered. The filter cake was dried under vacuum to give the title compound. MS (ESI, pos. ion·) m/z: 15 1 (Μ+1) 〇

(b)4-(6-氣基嘧啶-4-基氧基）-1Η-苯并[d]咪唑-2(3H)-酮。令 得自上述步驟（a)之4-羥基-1H-苯并[d]咪唑_2(3H)_酮（150 99461.doc -63- 1295670 mg，1 mmol)與 4,6_ 二氣基嘧啶（149 mg，1 mm〇1，AldHeh) 於實例34(a)的條件下進行反應，生成標題化合物。MS(ESI， pos· ion·) m/z: 263 (M+1)。(b) 4-(6-Gasylpyrimidin-4-yloxy)-1 fluorene-benzo[d]imidazole-2(3H)-one. 4-hydroxy-1H-benzo[d]imidazole-2(3H)-one (150 99461.doc -63 - 1295670 mg, 1 mmol) and 4,6-dioxapyrimidine obtained from the above step (a) (149 mg, 1 mm 〇1, AldHeh) The reaction was carried out under the conditions of Example 34 (a) to give the title compound. MS (ESI, pos· ion·) m/z: 263 (M+1).

(c)4-(6-(4-(l-(4_氟苯基）乙基）六氫吼畊-1_基）喷咬基氧 基）·1Η-苯并[d]咪唑-2(3H)-酮。令得自上述（b)之4-(6-氣基 嘧啶-4-基氧基）·1Η-苯并[d]咪唑-2(3H)-酮（45 mg，0.17 mmol)與1-(1 _(4_氟苯基）乙基）六氫吼畊、實例2(b)、（42 mg，0.2 mmol)於實例28(b)之條件下進行反應，生成白色非 結晶固體之標題化合物。MS (ESI，pos· ion.) m/z: 43 5 ·2 (M+1)° 實例45(c) 4-(6-(4-(l-(4-)Phenylphenyl)ethyl)hexahydroindole-1_yl) acetonyloxy)·1Η-benzo[d]imidazole-2 (3H)-ketone. 4-(6-Gasylpyrimidin-4-yloxy)·1Η-benzo[d]imidazole-2(3H)-one (45 mg, 0.17 mmol) and 1-(from the above (b) 1 _(4-Fluorophenyl)ethyl)hexahydroindole, Example 2(b), (42 mg, 0.2 mmol) was reacted under the conditions of Example 28 (b) to give the title compound as a white crystalline solid. . MS (ESI, pos. ion.) m/z: 43 5 ·2 (M+1)° Example 45

(a)2-曱基-1H-苯并[d]咪唆-4-醇。令2,3-二胺基紛（620 mg， 5 mmol，Aldrich)與冰醋酸（5 mL)之混合物於200°C微波爐 合成器中加熱5 min。令反應混合物冷卻至室溫並真空蒸 發，生成黑色油之標題化合物。MS(ESI，pos. ion.) m/z: 149.2 (M+1) 〇 9946I.doc • 64- 1295670(a) 2-mercapto-1H-benzo[d]imidon-4-ol. A mixture of 2,3-diamine (620 mg, 5 mmol, Aldrich) and glacial acetic acid (5 mL) was heated in a 200 °C microwave synthesizer for 5 min. The reaction mixture was cooled to room temperature and evaporated in vacuo to afford title crystal MS (ESI, pos. ion.) m/z: 149.2 (M+1) 〇 9946I.doc • 64- 1295670

cVyc N^N ^ (b)M6-氣基嘧啶-4-基氧基）-2-甲基·1Η-苯并[d]咪唑。令得 自上述步驟（a)之2-甲基_1H-苯并[d]咪唑·4_醇（148 mg，丄 mmol)與 4,6-二氣基嘧啶（148 mg，1 mmol，Aldrich)於實例 34(a)的條件下進行反應，生成黃色非結晶固體之標題化合 物。MS(ESI，pos. ion.) m/z: 261 (M+1)。cVyc N^N ^ (b) M6-oxapyrimidin-4-yloxy)-2-methyl·1Η-benzo[d]imidazole. 2-methyl-1H-benzo[d]imidazole-4-alcohol (148 mg, 丄mmol) and 4,6-dioxapyrimidine (148 mg, 1 mmol, Aldrich) from step (a) above The reaction was carried out under the conditions of Example 34 (a) to give the title compound as a yellow amorphous solid. MS (ESI, pos. ion.) m/z: 261 (M+1).

(c)4-(6_(4-(l-(4-氟苯基）乙基）六氫啦畊-i-基）嘧咬_4_基氧 基）-2-甲基-1H-苯并[d]咪唑。令得自上述步驟（b)之4-(6-氣 基嘧啶-4·基氧基）-2-甲基-1H-苯并[d]咪唑（30 mg，0,12 mmol)與1_(1_(4_氟苯基）乙基）六氫啦畊、實例2(b)、（0·15 mmol)於實例37(b)之條件下進行反應，生成油狀之標題化 合物。MS(ESI，pos. ion·) m/z: 433.2 (M+1)。 實例46(c) 4-(6-(4-(l-(4-fluorophenyl)ethyl)hexahydro-plow-i-yl)pyrimidine_4_yloxy)-2-methyl-1H-benzene And [d] imidazole. 4-(6-Amphetylpyrimidin-4-yloxy)-2-methyl-1H-benzo[d]imidazole (30 mg, 0,12 mmol) and 1_(from the above step (b) 1_(4-Fluorophenyl)ethyl)hexahydro-plowing, Example 2 (b), (0.15 mmol). MS (ESI, pos. ion·) m/z: 433.2 (M+1). Example 46

ClvTi^T&quot;°ClvTi^T&quot;°

Nv^N (a)7-(6 -氯基喊°定-4 -基氧基）-1Η-,σ朵。令7 -經基叫卜朵（400 111吕，3 111111〇卜8711(：]^111)與4,6-二氣基嘧啶（45〇11^，3 111111〇1， Aldrich)於實例34(a)的條件下進行反應，生成白色固體之標 題化合物。MS(ESI，pos· ion·) m/z: 246·1 (M+1)。 99461.doc -65- 1295670Nv^N (a) 7-(6-Chloro-cyclo-decyl-4-yloxy)-1Η-, σ.令 7 - 经基基卜朵 (400 111 吕, 3 111111〇卜 8711 (:]^111) and 4,6-dioxapyrimidine (45〇11^, 3 111111〇1, Aldrich) in Example 34 ( The reaction was carried out to give the title compound as a white solid. MS (ESI, pos· ion·) m/z: 246·1 (M+1). 99461.doc -65- 1295670

(b)7-(6-(4-(l-(4_氟苯基）乙基）六氫啦畊-1-基）嘧啶_4_基氧 基）_1Η-吲哚。令得自上述步驟（a)之7-(6-氣基嘧啶-4-基氧 基）-lH-吲哚（95 mg，0.39 mmol)與1-(1-(4_氟苯基）乙基）六 氫咕畊、實例2(b)、（85 mg，0·4 mmol)於實例37(b)之條件 下進行反應，生成無色固體之標題化合物。MS(ESI，pos. i〇n·) m/z: 418.2 (M+1)。 實例47(b) 7-(6-(4-(l-(4-Fluorophenyl)ethyl)hexahydro-peng-1-yl)pyrimidin-4-yloxy)_1Η-吲哚. 7-(6-Vyperylpyrimidin-4-yloxy)-lH-indole (95 mg, 0.39 mmol) and 1-(1-(4-fluorophenyl)-B obtained from the above step (a) The hexahydroindole, Example 2 (b), (85 mg, 0.4 mmol) was taken to give the title compound as a colourless solid. MS (ESI, pos. i 〇n) m/z: 418.2 (M+1). Example 47

(a) 6-(6-氣基嘴唆-4-基氧基）-1 H-°弓丨嗓。令6-經基e朵（266 mg，2 mmo 卜 Peakdale)與 4,6-二氣基嘧啶（298 mg，2 mmol， Aldrich)於實例28(a)的條件下進行反應，生成無色油之標題 化合物。MS(ESI，pos· ion·) m/z: 246.2 (M+1)。(a) 6-(6-Gas-based oxime-4-yloxy)-1 H-° bow. 6-Phase e (266 mg, 2 mmo, Peakdale) and 4,6-dioxapyrimidine (298 mg, 2 mmol, Aldrich) were reacted under the conditions of Example 28 (a) to give a colorless oil. Title compound. MS (ESI, pos· ion·) m/z: 246.2 (M+1).

(b )5-(6-(4-(1-(4苯基）乙基）六氫α比啡-i-基）嘴咬_4_基氧 基）-1Η-吲哚。令得自上述步驟（a)之6_(6_氣基嘧啶-4-基氧 基）-1Η-吲哚（123 mg，0.5 mmol)與1-(1-(4-氟苯基）乙基）六 氫口比畊、實例2(b)、（104 mg，0·5 mmol)於實例28(b)之條件 下進行反應，生成灰白色固體之標題化合物。MS(ESI，pos. ion·) m/z: 418 (M+1)。 99461.doc •66- 1295670 實例48(b) 5-(6-(4-(1-(4phenyl)ethyl)hexahydro-α-pyridyl-i-yl) mouth biting _4_yloxy)-1Η-吲哚. 6-(6-Azinopyrimidin-4-yloxy)-1Η-indole (123 mg, 0.5 mmol) and 1-(1-(4-fluorophenyl)ethyl group obtained from the above step (a) The hexahydro port was subjected to the reaction of Example 2 (b), (104 mg, 0.5 mmol MS (ESI, pos. ion·) m/z: 418 (M+1). 99461.doc •66- 1295670 Example 48

(a)8-(6-氣基喊唆-4-基氧基）H-咪峻[l，2-a]4b^。令味嗤 喝[l，2-a] 口比啶-8-醇（67 mg，0.5 mmol，根據 WO 2004/014871 所述製成）與4,6-二氣基嘧啶（75 mg，0.5 mmol，Aldrich)於 實例34(a)的條件下進行反應，生成無色膜之標題化合物。 MS(ESI，pos. ion·) m/z: 247 (M+1)。(a) 8-(6-Gas-based 唆-4-yloxy)H-misome [l,2-a]4b^. Let Miso drink [l,2-a] pyridine-8-ol (67 mg, 0.5 mmol, prepared according to WO 2004/014871) and 4,6-dioxapyrimidine (75 mg, 0.5 mmol) The reaction was carried out under the conditions of Example 34 (a) to give the title compound as a colorless film. MS (ESI, pos. ion·) m/z: 247 (M+1).

(b)8-(6-(4-(l-(4_氟苯基）乙基）六氫ϋ比π井-；μ基）嘴唆_4-基氧 基）Η·咪唑[l，2_a]吡啶。得自上述步驟（a)之8-(6-氣基嘧啶 -4-基氧基）H-咪唑[l，2-a]吡啶（25 mg，0·1 mmol)與 1-(1-(4-氟本基）乙基）六氫σ比1^井、實例2(b)、（25 mg，0· 12 mmol)於 實例37(b)之條件下進行反應，生成黃色膜之標題化合物。 MS(ESI，pos. ion.) m/z: 419.3 (M+1)。 實例49(b) 8-(6-(4-(l-(4-fluorophenyl)ethyl)hexahydroindole ratio π well-; μ-based) 唆4-yloxy) Η·imidazole [l, 2_a] pyridine. 8-(6-Gasylpyrimidin-4-yloxy)H-imidazole [l,2-a]pyridine (25 mg, 0.11 mmol) and 1-(1-() obtained from the above step (a) 4-fluorobenzyl)ethyl)hexahydro-sigma ratio 1^ well, Example 2(b), (25 mg, 0·12 mmol) was reacted under the conditions of Example 37 (b) to give the title compound as a yellow film. . MS (ESI, pos. ion.) m/z: 419.3 (M+1). Example 49

0)4-(6-氯基嘧啶-4-基氧基）-1Η-吲哚。令4-羥基吲哚（133 mg，1 mmol，Aldrich)與 4,6-二氯基嘧啶（185 mg，1.25 mmol，Aldrich)於實例34(a)的條件下進行反應，生成黃色 固體之標題化合物。MS(ESI，pos· ion·) m/z: 246 (M+1)。 99461.doc -67- 12956700) 4-(6-Chloropyrimidin-4-yloxy)-1Η-oxime. 4-Hydroxyindole (133 mg, 1 mmol, Aldrich) was reacted with 4,6-dichloropyrimidine (185 mg, 1.25 mmol, Aldrich) under the conditions of Example 34 (a) to give a yellow solid title Compound. MS (ESI, pos· ion·) m/z: 246 (M+1). 99461.doc -67- 1295670

FF

(b)4-(6_(4-(l-(4-氟苯基）乙基）六氫。比啡-1-基）嘧啶-4-基氧 基）-1Η-吲哚。令得自上述步驟（a)之4-(6-氣基嘧啶-4-基氧 基）-1Η-吲哚（200 mg，0.8 mmol)與1-(1·(4·氟苯基）乙基）六 氫σ比啡、實例2(b)、（167 mg，0.8 mmol)於實例28(b)之條件 下進行反應，生成105 mg(32%)白色非結晶固體之標題化合 物。MS(ESI，pos. ion·) m/z: 418.2 (M+1)。 實例50(b) 4-(6-(4-(l-(4-Fluorophenyl)ethyl)hexahydro.picin-1-yl)pyrimidin-4-yloxy)-1Η-oxime. 4-(6-Amphetylpyrimidin-4-yloxy)-1Η-indole (200 mg, 0.8 mmol) and 1-(1·(4·fluorophenyl)B obtained from the above step (a) The reaction of the hexahydro-pyridinium, the compound of Example 2 (b), (167 mg, 0.8 mmol) was carried out under the conditions of Example 28 (b) to give the title compound. MS (ESI, pos. ion·) m/z: 418.2 (M+1). Example 50

(a)5-羥基-1H-苯并[d]咪唑-2(3H)-酮。將1M三氣化鋁之硝基 苯（1 mL，1 mmol，Aldrich)加入 5 -曱氧 1H-苯并[d] σ米嗤 -2(3 Η)-酮（164 mg，1 mmol，Lane aster)之 DCM(2 mL)溶液。 令該反應混合物於室溫攪拌4天，並真空蒸發。令殘渣濾過 Celite®，並令濾塊經DCM洗。丟棄DCM洗液，並以MeOH 洗濾塊。收集暗棕色之Me OH洗液，並減壓蒸發。令殘潰經 矽膠管柱色析（梯度：5-20% MeOH/CH2Cl2)純化，生成淡黃 色固體之標題化合物。MS(ESI，pos· ion·) m/z: 151 (M+1)。(a) 5-Hydroxy-1H-benzo[d]imidazole-2(3H)-one. Add 1M tri-aluminum nitrobenzene (1 mL, 1 mmol, Aldrich) to 5-oxo 1H-benzo[d] σ m嗤-2(3 Η)-one (164 mg, 1 mmol, Lane Aster) DCM (2 mL) solution. The reaction mixture was stirred at room temperature for 4 days and evaporated in vacuo. The residue was filtered through Celite® and the filter was washed with DCM. The DCM wash was discarded and the filter pad was washed with MeOH. The dark brown Me OH wash was collected and evaporated under reduced pressure. The residue was purified by EtOAc (EtOAc:EtOAc:EtOAc: MS (ESI, pos· ion·) m/z: 151 (M+1).

(b)5-(6-氯基嘧啶-4-基氧基）-1Η-苯并[d]咪唑-2(3H)-酮。令 99461.doc -68- 1295670 得自上述步驟（a)之5_經基 (1 OOmg，0.66 mmol)與 4,6-二 ι (lOOmg，0.66 mm〇1)與 4,6_ 二氣基嘧啶（ι〇5 叫，〇 7 麵〇卜(b) 5-(6-Chloropyrimidin-4-yloxy)-1 fluorene-benzo[d]imidazole-2(3H)-one. 99461.doc -68- 1295670 from the above step (a) 5_ mercapto (100 mg, 0.66 mmol) and 4,6-di(lOOmg, 0.66 mm〇1) and 4,6-dioxapyrimidine (ι〇5 叫,〇7 〇 〇

Aldnch)於實例34⑷的條件下進行反應，生成膜之標題化合 物。MS(ESI，pos. i0n.) m/z: 263 (Μ+ι)。Aldnch) was reacted under the conditions of Example 34 (4) to give the title compound of the film. MS (ESI, pos. i0n.) m/z: 263 (Μ+ι).

ΟΟ

(c)5-(6_(4-(l-(4-氟苯基）乙基）六氫吼_ _卜基）嘧啶基氧 基）-1Η-苯并[d]咪唑-2(3Η)-酮。令得自上述步驟（b)之5-(6-氣基哺咬_4_基氧基）_1H-苯并[d]咪嗤·2(3Η)_酮（95 mg，0·37 mmol)與1_(1_(4·氣苯基）乙基）六氫吨哨：、實例2(b)、（80 mg，0.3 8 mmol)於實例28(b)之條件下進行反應，生成淡黃 色非結晶固體之標題化合物。MS(ESI，pos. ion.) m/z: 435.2 (M+l) 〇 實例51(c) 5-(6-(4-(l-(4-fluorophenyl)ethyl)hexahydroindole__byl)pyrimidinyloxy)-1Η-benzo[d]imidazole-2(3Η) -ketone. 5-(6-Gas-based _4_yloxy)_1H-benzo[d]methane·2(3Η)-one (95 mg, 0·37 mmol) obtained from the above step (b) Reaction with 1_(1_(4·gasphenyl)ethyl)hexahydro ton:, Example 2(b), (80 mg, 0.38 mmol) under the conditions of Example 28(b) to give a pale yellow The title compound of the crystalline solid. MS (ESI, pos. ion.) m/z: 435.2 (M+l) 实例 Example 51

(a)5-(6-氣基嘧啶-4-基氧基）-3,3-二甲基吲哚啉-2-酮。令5· 备基-3,3-二甲基°弓卜朵琳-2-_(177 11^，1111111〇1，^11了6。11) 與 4,6-二氣基嘧唆（149 mg，1 mmol，Aldrich)於實例34(a) 的條件下進行反應，生成油狀之標題化合物。MS(ESI，pos· i〇n·) m/z: 290 (M+1)。 99461.doc -69- 1295670(a) 5-(6-Gasylpyrimidin-4-yloxy)-3,3-dimethylindol-2-one.令5·备基-3,3-Dimethyl°弓布多琳-2-_(177 11^,1111111〇1,^11,6.11) with 4,6-dioxapyrimidine (149 The reaction was carried out in the title compound (m. MS (ESI, pos· i〇n·) m/z: 290 (M+1). 99461.doc -69- 1295670

(b)5-(6-(4-( 1-(4-氟苯基）乙基）六氫°比畊-1_基）嘧啶-4-基氧 基）-3,3-二甲基吲哚啉-2-酮。令得自上述步驟（a)之5-(6-氣 基喊咬-4-基氧基）-3,3-二甲基°引σ朵琳-2-酮（56 mg，0.2 mmol) 與1-(1-(4-氟苯基）乙基）六氫吡畊、實例2(b)、（40 mg，0.19 mmol)於實例28(b)之條件下進行反應，生成無色固體之標 題化合物。MS(ESI, pos· ion·) m/z: 462.2 (M+1)。 實例52(b) 5-(6-(4-(1-(4-fluorophenyl)ethyl)hexahydro-ratio-1-yl)pyrimidin-4-yloxy)-3,3-dimethyl Porphyrin-2-one. 5-(6-gas-based ketone-4-yloxy)-3,3-dimethyl-methyl-pyridyl-2-one (56 mg, 0.2 mmol) obtained from the above step (a) 1-(1-(4-Fluorophenyl)ethyl)hexahydropyrazine, Example 2(b), (40 mg, 0.19 mmol) was obtained under the conditions of Example 28 (b) to give a colorless solid title Compound. MS (ESI, pos· ion·) m/z: 462.2 (M+1). Example 52

(a)4-(6-氣基嘧啶-4-基氧基）苯并[d]噻唑-2-胺。令2-胺基苯 并[d]嚷嗤-4-醇（166 mg’ 1 mmol，Carbogen)與 4,6-二氣基 嘧唆（150 mg，1 mmol，Aldrich)於實例34(a)的條件下進行 反應，生成白色固體之標題化合物。MS(ESI，pos. ion.) m/z: 279 (M+1) 〇(a) 4-(6-Gasylpyrimidin-4-yloxy)benzo[d]thiazole-2-amine. 2-Aminobenzo[d]indol-4-ol (166 mg '1 mmol, Carbogen) and 4,6-dioxapyrimidine (150 mg, 1 mmol, Aldrich) in Example 34(a) The reaction was carried out to give the title compound as a white solid. MS (ESI, pos. ion.) m/z: 279 (M+1) 〇

(b)4-(6-(4-(l-(4-氟苯基）乙基）六氫吼啩-丨·基）嘧啶基氧 基）苯并[d]噻唑-2-胺。令得自上述步驟之4-(6-氣基嘧咬 _4_基氧基）苯并[d]噻唑胺（15〇 mg，〇·54 mmol)與 1-(1_(4· 敦苯基）乙基）六氫吡畊、實例2(b)、（115 mg，0·55 mmol: 1295670 於實例28(b)之條件下進行反應，生成非結晶固體之標題化 合物。MS(ESI，pos. ion·) m/z: 451.2 (M+1)。 實例53(b) 4-(6-(4-(l-(4-Fluorophenyl)ethyl)hexahydroindole-indolyl)pyrimidinyloxy)benzo[d]thiazole-2-amine. 4-(6-Azylpyridinyl-4-yloxy)benzo[d]thiazolamine (15 mg, 〇·54 mmol) and 1-(1_(4· phenyl) obtained from the above steps Ethyl) hexahydropyrazine, Example 2 (b), (115 mg, 0. 55 mmol: 1295670) The title compound was obtained as the title compound (m. Ion·) m/z: 451.2 (M+1). Example 53

C02Me (a)2-羥基-6-(2-甲氧基-2-氧基乙基）苄酸。逐滴將氯化乙醯 攪拌下加入0°C之3-羥基同鄰苯二甲酸（4.5 g，23 mmol， Apin)之MeOH(100 mL)溶液。令反應混合物於室溫攪拌 1 8h，並減壓蒸發溶劑，提供白色固體之標題化合物。1Η NMR (400 MHz, DMSO-d6) δ ppm: 3.57 (s, 3H), 3.84 (s5 2H), 6·78 (d，J=7.43 Hz，1H)，6.86 (d，J=8.22 Hz, 1H)，7.32 (t， J=7.82 Hz，1H)。C02Me (a) 2-hydroxy-6-(2-methoxy-2-oxyethyl)benzyl acid. A solution of 3-hydroxyphthalic acid (4.5 g, 23 mmol, Apin) in MeOH (100 mL) was added dropwise with stirring. The reaction mixture was stirred with EtOAc EtOAc m. 1 NMR (400 MHz, DMSO-d6) δ ppm: 3.57 (s, 3H), 3.84 (s5 2H), 6·78 (d, J = 7.43 Hz, 1H), 6.86 (d, J = 8.22 Hz, 1H ), 7.32 (t, J = 7.82 Hz, 1H).

(b)8-羥基-1H-異咣烷烯-3(4H)-酮。將硼烷-甲基硫化物複合 物之 THF溶液（25 mL，50 mmol，2·0Μ，Aldrich)於室溫、 乂氣壓下攪拌加入得自上述步驟（a)之2-羥基-6-(2-曱氧基 -2-氧基乙基）苄酸（4.2 g，20 mmol)之無水THF(10 mL)溶 液。令反應混合物廻流攪拌3.5h，令其冷卻至25°C並緩慢 添加5NHCl(20mL)終止反應。完全添加後，令該反應混合 物廻流加熱10分鐘，並令其冷卻至25°C。令混合物真空濃 縮至體積〜5 0 mL，以水（200 mL)稀釋，經EtOAc萃取（2x200 mL)。令合併之有機萃取物經飽和NaCl(100 mL)洗，Na2S04 99461.doc -71- 1295670 乾燥，過濾並真空濃縮，提供白色固體。令該固體經矽膠 管柱色析（梯度：15-50% EtOAc之己烷溶液）純化，提供白色 固體之標題化合物。NMR (400 MHz，DMSO_d6) δ ppm: 3.52 (s，2Η)，5.11 (s，2Η)，6.54 (d，J=7.43 Ηζ，1Η)，6.57 (d， J=8.22 Hz，1H)，6·94 (t，J=7.63 Hz，1H)，9.72 (s，1H)。(b) 8-Hydroxy-1H-isodecenyl-3(4H)-one. The borane-methyl sulfide complex THF solution (25 mL, 50 mmol, 2.0 Å, Aldrich) was added to the 2-hydroxy-6- (from the above step (a) by stirring at room temperature under a helium pressure. A solution of 2-nonyloxy-2-oxyethyl)benzyl acid (4.2 g, 20 mmol) in dry THF (10 mL). The reaction mixture was stirred with stirring for 3.5 h, then cooled to 25 &lt;0&gt;C and slowly quenched with 5N HCl (20 mL). After complete addition, the reaction mixture was turbulently heated for 10 minutes and allowed to cool to 25 °C. The mixture was concentrated in vacuo to EtOAc (EtOAc) (EtOAc) The combined organic extracts were dried with EtOAc EtOAc m. The solid was purified by EtOAc (EtOAc:EtOAc:EtOAc NMR (400 MHz, DMSO_d6) δ ppm: 3.52 (s, 2 Η), 5.11 (s, 2 Η), 6.54 (d, J = 7.43 Ηζ, 1 Η), 6.57 (d, J = 8.22 Hz, 1H), 6· 94 (t, J = 7.63 Hz, 1H), 9.72 (s, 1H).

HH

HO (c)8-羥基-1，2-二氫異喹啉-3(4H)-酮。[類似下述方法：White， Ε· Η·; Roswell，D· F·; Politzer，I· R·; Branchini，B. R. ActiveHO (c) 8-hydroxy-1,2-dihydroisoquinoline-3(4H)-one. [Similar to the following methods: White, Ε· Η·; Roswell, D·F·; Politzer, I·R·; Branchini, B. R. Active

Site-Directed Inhibition with Substrates Producing Carbonium Ions: Chymotrypsin. Methods Enzym, 1977(46)， 216-220]。令得自上述步驟（b)之8-羥基-1H-異咣烷烯-3 (4H)-酮（1.0 g，6.1 mmol)與尿素（2.2 g，37 mmol，Aldrich) 之混合物於200°C油浴攪拌下加熱30 min。令反應混合物 冷卻至25°C，經IN HC1(50 mL)與DCM(50 mL)處理，並攪 拌5h ’提供懸浮液。過濾該懸浮液，並令濾塊經1N HC1(50 mL)、水（5 0 mL)與dcM(50 mL)洗。令合併之DCM洗液與濾 液經飽和NaCl(3〇 mL)洗，並減壓蒸發。令殘渣真空乾燥， 提供棕色固體之標題產物。iH NMR (400 MHz，DMSO-d6) δ ppm: 3.36 (s，2Η)，4·23 (s，2Η)，6·61 (d，J=7.43 Ηζ，1Η)， 6·68 (d，J=7.82 Hz，1H)，7·03 (t，J=7.83 Hz，1H)，7.92 (s，1H)， 9.66 (s，1H) 〇 99461.docSite-Directed Inhibition with Substrates Producing Carbonium Ions: Chymotrypsin. Methods Enzym, 1977 (46), 216-220]. A mixture of 8-hydroxy-1H-isodecenen-3(4H)-one (1.0 g, 6.1 mmol) and urea (2.2 g, 37 mmol, Aldrich) from step (b) above at 200 ° C Heat in an oil bath for 30 min with stirring. The reaction mixture was cooled to 25 &lt;0&gt;C, EtOAc (50 mL) and DCM (50 mL) The suspension was filtered and the filter was washed with 1N EtOAc (50 mL), water (50 mL) and EtOAc (50 mL). The combined DCM washes and filtrate were washed with saturated NaCl (3 mL) and evaporated. The residue was dried in vacuo to give the title product as a brown solid. iH NMR (400 MHz, DMSO-d6) δ ppm: 3.36 (s, 2Η), 4·23 (s, 2Η), 6.61 (d, J=7.43 Ηζ, 1Η), 6.68 (d, J =7.82 Hz,1H),7·03 (t,J=7.83 Hz,1H), 7.92 (s,1H), 9.66 (s,1H) 〇99461.doc

-72- 1295670-72- 1295670

(d)(S)-8-(6-(4-(l-(4_氟苯基）乙基）六氫。比畊-1-基）嘧啶-4-基 氧基）-1，2-二氫異喧琳-3 (4Η)-酮鹽酸鹽。令得自上述步驟（c) 之8-羥基-1，2-二氣異喧琳- 3(4Η)-酮（200 mg，1.2 mmol)之無 水DMF(5 mL)溶液經N2淨化，並經顆粒K2C03(1 g，7.2 mmol，Aldrich)與 4,6-二氟基喂唆（140 mg，1 ·2 mmol，ABCR) 處理。令反應混合物於25 °C經磁性攪拌lh。添加 l-[(l_S)-l-(4-亂基-苯基）-乙基]-六鼠 0比味（200 mg ’ 0.96 mmol，如實例27所述製成），並令混合物於50°C授拌加熱30 min。令反應混合物達室溫並經EtOAc(100 mL)稀釋。將 EtOAc溶液由固體K2C03倒出，經飽和NaHCO3(50 mL)溶 液、水（50 mL)洗、飽和NaCl(50 mL)洗，經Na2S04乾燥與 過渡。真空蒸發渡液，並令殘渣經石夕膠管柱色析（梯 度：l-10%MeOH/EtOAc)純化，提供固體之純產物。溶該固 體於 EtOAc(50 mL)與 MeOH(5 mL)，並經 IN HC1 之 Et2O(20 mL，Aldrich)處理。令該混合物減壓蒸發，並令殘渣真空 乾燥，提供淡黃色非結晶固體之標題化合物。MS(ESI，pos. ion.) m/z: 448 (M+1)。C25H26N5F02· 1.8 HC1.0.8H2O分析計 算值：C，56·92; H，5.62; N，13.28; Cl，12.10; F，3.60。發現 值：C，56.60; H，5.80; N，12.91; Cl，12.00; F，3.51 〇 實例54 99461.doc -73- 1295670(d) (S)-8-(6-(4-(l-(4-fluorophenyl)ethyl)hexahydro. Specific cultivating-1-yl)pyrimidin-4-yloxy)-1,2 - Dihydroisoindolin-3 (4Η)-ketone hydrochloride. The solution of 8-hydroxy-1,2-dioxaisoline-3(4Η)-one (200 mg, 1.2 mmol) in anhydrous DMF (5 mL) obtained from the above step (c) was purified by N? Granules K2C03 (1 g, 7.2 mmol, Aldrich) were treated with 4,6-difluoro-based hydrazine (140 mg, 1.2 mmol, ABCR). The reaction mixture was magnetically stirred at 25 ° C for 1 h. Add l-[(l_S)-l-(4-ranyl-phenyl)-ethyl]-six mouse 0 odor (200 mg '0.96 mmol, prepared as described in Example 27) and let the mixture at 50 Heat the mixture at °C for 30 min. The reaction mixture was allowed to come to EtOAc EtOAc (EtOAc) The EtOAc solution was poured from aq. EtOAc (EtOAc)EtOAc. The liquid was evaporated in vacuo, and the residue was purified eluted eluted eluted elut elut elut elut elut elut The solid was taken up in EtOAc (50 mL) EtOAc (EtOAc) The mixture was evaporated under reduced pressure to dryness crystals crystals MS (ESI, pos. ion.) m/z: 448 (M+1). </ RTI> <RTIgt; Found: C, 56.60; H, 5.80; N, 12.91; Cl, 12.00; F, 3.51 〇 Example 54 99461.doc -73- 1295670

(a)3-甲氧基苯·1，2-二胺二鹽酸鹽。令3-曱氧基-2-硝基-苯 胺、實例25(a)、（18.0 g，107 mmol)、Pd/C(10 wt%，1.8 g， 1 ·7 mmol，Aldrich)與 MeOH( 130 mL)於 H2 氣壓下撥拌 40h。 令混合物濾過Celite®並真空濃縮濾液。溶殘渣於Et20並經 1M HC1 之 Et20處理（23 0 mL，23 0 mmol，Aldrich)。過遽收 集固體並以Et20洗。分開濾塊並真空乾燥，生成淡粉紅色 粉末之標題化合物。MS(ESI，pos· ion·) m/z: 139(M-HC12_)。(a) 3-Methoxybenzene·1,2-diamine dihydrochloride. 3-methoxy-2-nitro-phenylamine, Example 25(a), (18.0 g, 107 mmol), Pd/C (10 wt%, 1.8 g, 1 ·7 mmol, Aldrich) and MeOH (130 mL) Mix for 40 h under H2 pressure. The mixture was filtered through Celite® and the filtrate was concentrated in vacuo. The residue was taken up in Et20 and taken to 1M EtOAc (EtOAc) (EtOAc (EtOAc) The solid was collected and washed with Et20. The filter blocks were separated and dried in vacuo to give the title compound as a pale pink powder. MS (ESI, pos ion) m/z: 139 (M-HC12).

(b)8-甲氧基-1H-喹嘮啉-2酮與5-甲氧基-1H-喹呤啉-2-酮。 令得自上述步驟（a)之3-甲氧基苯-1，2-二胺二鹽酸鹽（5.28 g，25 mmol)之 EtOH(30 mL)與 H2O(70 mL)溶液經小心添加 固態NaHC03而中和。添加乙醛酸乙酯（50%，5.45 mL，27.5 mmol，Fluka)溶液，並令混合物於室溫擾拌24h。令混合物 經飽和NH4C1稀釋，並經25%i-PrOH/CHCl3萃取（4x)。令合 併之有機萃取物經Na2S04乾燥，過濾並真空蒸發。藉由管 柱色析（梯度：〇-2·5%2ΜΝΗ3之MeOH/CH2Cl2)純化，提供8-甲氧基-1H-喹嘮啉-2-酮之灰白粉末[MS(ESI，pos. ion·) m/z: 177 (M+l)]與5-甲氧基-1H-喹哼啉-2-酮之灰白粉末 [MS(ESI，pos· ion.) m/z: 177 (M+1)]。 99461.doc -74- 1295670 OMe 0c；r (c)2-氣基-8-曱氧基-喹噚啉。令得自上述（b)之8-曱氧基-1H-喹哼啉-2-酮（5.34 g，30.3 mmol)與 POC13(100 mL，1073 mmol，Aldrich)混合物加熱至105°C達4h。令反應混合物冷 卻至室溫並真空蒸發。令殘渣於飽和NaHC03溶液與CH2C12 之間進行區分，並攪拌3h。分開CH2C12層，並以CH2C12萃 取水相（3x)。合併CH2C12萃取物，經Na2S04乾燥，並濾過 矽膠片。令濾塊經EtOAc洗，並合併濾液。蒸發溶劑生成固 體殘渣，令其真空乾燥以提供標題化合物。MS(ESI，pos. ion.) m/z: 195 (Μ+1) 〇 OMe 6c；r (d)8 -甲氧基-哇p亏淋-2-基胺。令得自上述步驟（c)之2 -氣基 -8-曱氧基-喹嘮啉（5.75 g，29.5 mmol)、濃 NH4OH(30 mL， Baker)與EtOH(3 mL)混合物於壓力容器中加熱至110°C達 28h。令反應混合物冷卻至室溫並以H20稀釋。過濾固體殘 渣，並以H20洗。令濾塊經短的矽膠管柱純化，以1% MeOH/CH2Cl2(500 mL)與 10% MeOH/CH2Cl2(500 mL)溶 離。分開第二個部分並真空蒸發。令固體殘渣經MeOH再結 晶，生成標題化合物。MS(ESI，pos. ion·) m/z: 1 76 (M+1)。(b) 8-Methoxy-1H-quinoxaline-2 ketone and 5-methoxy-1H-quinoxalin-2-one. A solution of EtOH (30 mL) and H2O (70 mL) from 3-methoxybenzene-1,2-diamine dihydrochloride (5.28 g, 25 mmol) from step (a) Neutralized with NaHC03. A solution of ethyl glyoxylate (50%, 5.45 mL, 27.5 mmol, Fluka) was added and the mixture was stirred at room temperature for 24 h. The mixture was diluted with saturated NH.sub.4Cl.sub.1 and extracted with &lt;RTI ID=0.0&gt;&gt; The combined organic extracts were dried over Na2SO4, filtered and evaporated in vacuo. Purification by column chromatography (gradient: 〇-2·5% 2 ΜΝΗ3 of MeOH/CH 2 Cl 2) affords white powder of 8-methoxy-1H-quinoxalin-2-one [MS (ESI, pos. ·) m/z: 177 (M+l)] with 5-methoxy-1H-quinoxalin-2-one as an off-white powder [MS (ESI, pos. ion.) m/z: 177 (M+ 1)]. 99461.doc -74- 1295670 OMe 0c;r (c) 2-Alkyl-8-decyloxy-quinoxaline. The mixture of 8-methoxy-1H-quinoxalin-2-one (5.34 g, 30.3 mmol) from POB13 (100 mL, 1073 mmol, Aldrich) obtained from above (b) was heated to 105 ° C for 4 h. The reaction mixture was cooled to room temperature and evaporated in vacuo. The residue was partitioned between saturated NaHC03 solution and CH2C12 and stirred for 3 h. The CH2C12 layer was separated and the aqueous phase (3x) was extracted with CH2C12. The CH2C12 extract was combined, dried over Na2SO4, and filtered through EtOAc. The filter was washed with EtOAc and the filtrate was combined. The solvent was evaporated to give a solid residue which was dried in vacuo to afford title compound. MS (ESI, pos. ion.) m/z: 195 ( Μ +1) 〇 OMe 6c; r (d) 8 - methoxy-wow p-deoxy-2-ylamine. A mixture of 2-carbo-8-decyloxy-quinoxaline (5.75 g, 29.5 mmol), concentrated NH4OH (30 mL, Baker) and EtOH (3 mL) from the above step (c) in a pressure vessel Heat to 110 ° C for 28 h. The reaction mixture was allowed to cool to room temperature and diluted with H20. The solid residue was filtered and washed with H20. The filter was purified by a short hydrazine column eluting with 1% MeOH / CH.sub.2Cl.sub.2 (500 mL) and 10% MeOH/CH.sub.2Cl.sub.2 (500 mL). The second part was separated and evaporated in vacuo. The solid residue was recrystallized from MeOH to give the title compound. MS (ESI, pos. ion·) m/z: 1 76 (M+1).

OHOH

nh2 99461.doc -75- 1295670 (e)3-胺基-喹咩啉-5-醇。令得自上述步驟（d)之8-甲氧基-喹 噚啉-2-基胺（2·51 g，14·3 mmol)之 CH2C12(150 mL)混合物 經 BBr3(4.05 mL，43 mmol，Aldrich)處理，並加熱至 44°C 達6d。令該混合物冷卻至室溫，並以飽和NaHC03溶液終止 反應，並以25% i-PrOH/CHCl3萃取（5x)。令合併之有機萃取 物經Na2S04乾燥，過濾並蒸發。令殘渣真空乾燥生成標題 化合物。MS(ESI，pos· ion·) m/z: 162 (M+1)。Nh2 99461.doc -75- 1295670 (e) 3-Amino-quinoxaline-5-ol. A mixture of 8-methoxy-quinoxalin-2-ylamine (2·51 g, 14·3 mmol) from CH2C12 (150 mL) Aldrich) treatment and heating to 44 ° C for 6d. The mixture was allowed to cool to room temperature and quenched with saturated NaHC03 solution and extracted (2×) with 25% i-PrOH/CHCl3. The combined organic extracts were dried over Na2SO4 filtered and evaporated. The residue was dried under vacuum to give the title compound. MS (ESI, pos· ion·) m/z: 162 (M+1).

(f)8-(6-氯基嘧啶-4-基氧基）喹嘮啉-2-胺。令得自上述步驟 (e)之3-胺基-喧巧琳-5-醇（500 mg，3.1 mmol)與4,6_二氣基 口密唆（462 mg，3.1 mmol，Aldrich)於實例26(a)之條件下進 行反應，生成標題化合物。MS(ESI，pos. ion·) m/z: 274 (M+1)。(f) 8-(6-Chloropyrimidin-4-yloxy)quinoxalin-2-amine. Illustrative examples of the 3-amino-carboline-5-ol (500 mg, 3.1 mmol) from the above step (e) and 4,6-di-gas-based succinimide (462 mg, 3.1 mmol, Aldrich) The reaction was carried out under the conditions of 26 (a) to give the title compound. MS (ESI, pos. ion·) m/z: 274 (M+1).

(g)(S)-8-(6-(4-(l-(4_氟苯基）乙基）六氫啦畊-1-基）嘧啶-4-基 氧基）喹喏啉-2-胺。令得自上述步驟（f)之8-(6-氣基嘧啶-4-基氧基）喹嘮啉-2-胺（424 mg，1.55 mmol)與（S)-1-(1-(4-氟苯 基）乙基）六氫吼^7井（323 mg，1.5 5 mmol，根據實例27所述加 以製備）於實例26(b)之條件下進行反應，生成標題化合物。 99461.doc -76- 1295670 MS(ESI，pos· ion·) m/z: 446 (M+l) 0 Mp:114〇C 〇 實例55(g) (S)-8-(6-(4-(l-(4-Fluorophenyl)ethyl)hexahydro-peng-1-yl)pyrimidin-4-yloxy)quinoxaline-2 -amine. 8-(6-Gasylpyrimidin-4-yloxy)quinoxalin-2-amine (424 mg, 1.55 mmol) obtained from the above step (f) and (S)-1-(1-(4) -Fluorophenyl)ethyl)hexahydroindole^7 (323 mg, 1.55 mmol, mp. 99461.doc -76- 1295670 MS(ESI,pos· ion·) m/z: 446 (M+l) 0 Mp:114〇C 实例 Example 55

(R)-8-(6-(4-(l_(4 -氟苯基）乙基）六氫^1比畊-1-基）喊唆基氧 基）喹嘮啉-2-胺。 令實例54(f)之8-(6 -氣基喊唆-4-基氧基）啥巧琳_2_胺（424 mg，1.55 mmol)與實例 23(c)之（R)-l-(l-(4_ 氟苯基）乙基）六 氫°比p井（323 mg，1.55 mmol)於實例26(b)之條件下進行反 應，生成標題化合物。MS(ESI，pos. ion.) m/z: 446 (M+1)。 Mp:118〇C 〇 實例56(R)-8-(6-(4-(l_(4-fluorophenyl)ethyl)hexahydro^1 cultivating-1-yl) sulfhydryloxy)quinoxaline-2-amine. Example 8-(6-gas-based 唆-4-yloxy) 啥巧琳_2_amine (424 mg, 1.55 mmol) and Example 23(c) (R)-l- (l-(4-F-Phenylphenyl)ethyl)hexahydropyrene was reacted under the conditions of Example 26 (b) to give the title compound. MS (ESI, pos. ion.) m/z: 446 (M+1). Mp: 118〇C 〇 Example 56

(a)5-甲氧基喧崎淋-2,3(1H，4H)_二g同。令3-甲氧基苯_i，2_二 胺二鹽酸鹽（實例54(a))於10% Na2C〇3水溶液與ch2C12之間 進行區分。以CH^Ch萃取水層（2x)。令合併之有機萃取物經 NazSCU乾燥，過濾並蒸發而產生3-甲氧基苯-二胺。令 該二胺（912 mg，6.6 mmol)與草酸二乙酯（9.〇 mL，66 mmol，Aldrich)之混合物於185°C加熱18h。令該反應混合 物達室溫，並濾出固體沈澱物。濾塊經EtOH洗，並真空乾 燥而生成標題化合物。MS(ESI，pos· ion·) m/z: 191 (M+1)。 99461.doc -77· 1295670(a) 5-methoxy oxazinidine-2,3(1H,4H)_di-g. 3-Methoxybenzene-i,2-diamine dihydrochloride (Example 54(a)) was distinguished between 10% aqueous Na2C3 and CH2C12. The aqueous layer (2x) was extracted with CH^Ch. The combined organic extracts were dried over NazSCU, filtered and evaporated to give 3-methoxybenzene-diamine. A mixture of the diamine (912 mg, 6.6 mmol) and diethyl oxalate (9. 〇 mL, 66 mmol, Aldrich) was heated at 185 °C for 18 h. The reaction mixture was allowed to reach room temperature and the solid precipitate was filtered. The filter cake was washed with EtOH and dried in vacuo to give title compound. MS (ESI, pos· ion·) m/z: 191 (M+1). 99461.doc -77· 1295670

(b)5-羥基喹巧琳 _2,3(1H，4H)_ 二酮。將 BBr3(1.0M 之 CH2CI2 ’ 2.8 mL，2.8 mmol，Aldrich)力口入得自上述步驟⑷ 之 5-甲氧基·喹噚啉-2,3(1H，4H)-二酮（180 mg , 0.94 mg)之 CH2Ch(10 mL)溶液，並令該混合物於45°C加熱20h。令該 反應混合物達到室溫，並過濾固體沈澱物。以Me〇H洗濾塊 (3x)，並真空乾燥生成標題化合物MS(ESI，pos. ion·) m/z: 179 (M+l) 〇(b) 5-hydroxyquinoline _2,3(1H,4H)-dione. BBr3 (1.0 M CH2CI2 '2.8 mL, 2.8 mmol, Aldrich) was vigorously introduced into 5-methoxyquinoxaline-2,3(1H,4H)-dione (180 mg, from the above step (4). A solution of 0.94 mg) in CH.sub.2Ch (10 mL). The reaction mixture was allowed to reach room temperature and the solid precipitate was filtered. The filter cake (3x) was washed with MeOH (3×) and dried in vacuo to give the title compound MS (ESI, pos. ion·) m/z: 179 (M+l) 〇

(e)5-(6-氣基嘧啶-4-基氧基）喹嘮啉-2,3(1H，4H)-二酮。令得 自上述步驟（b)之5-羥基喹噚啉-2,3(1H，4H)-二酮（356 mg， 2·0 mmol)與 4,6-二氣基嘴唆（289 mg，2.0 mmol ’Aldrich) 於實例26(a)之條件下進行反應，生成標題化合物。(e) 5-(6-Aceylpyrimidin-4-yloxy)quinoxaline-2,3(1H,4H)-dione. 5-hydroxyquinoxaline-2,3(1H,4H)-dione (356 mg, 2.0 mmol) obtained from the above step (b) and 4,6-dipyrene ( 289 mg, 2.0 mmol 'Aldrich) The reaction was carried out under the conditions of Example 26 (a) to give the title compound.

(d)(R)_5-(6-(4-(1-(4 -亂苯基）乙基）六鼠°比p井-1 _基）♦唆·4-基氧基）喹噚啉-2,3(1H，4H)-二酮。令得自上述步驟（c)之 5-(6-氣基嘧啶-4-基氧基）喹吟啉-2,3(1H，4H)_二酮（100 mg，0·34 mmol)與實例 23(c)之（R)-l-(l-(4-氟苯基）乙基）六 氫吡畊（72 mg，0.34 mmol)於實例26(b)之條件下進行反 99461.doc -78- 1295670 應，生成標題化合物。MS(ESI，pos· ion.) m/z: 463 (Μ+l)。 實例57(d) (R)_5-(6-(4-(1-(4-)-)-yloxy)quinoxaline -2,3(1H,4H)-dione. 5-(6-Amphetylpyrimidin-4-yloxy)quinoxaline-2,3(1H,4H)-dione (100 mg, 0·34 mmol) obtained from the above step (c) and examples (R)-l-(l-(4-fluorophenyl)ethyl)hexahydropyridine (72 mg, 0.34 mmol) was subjected to the anti-99461.doc under the conditions of Example 26(b). 78- 1295670 should, generate the title compound. MS (ESI, pos. ion.) m/z: 463 (Μ+l). Example 57

OH Λ02 (a) 3,5-二氟基-2·硝基酚。將 10NNaOH(12 mL，120 mmol， JT Baker)加入 1，3,5 -三氟基-2_ 硝基苯（10 g，5.6 mmol， Aldrich)之DMSO(50 mL)溶液，並令該混合物於室溫攪拌 20h。令反應混合物經H20稀釋，並經Et20萃取。分開水層， 並經濃HC1酸化至pH 5，並經Et20萃取（2x)。令合併之有機 萃取物經鹽液洗，經Na2S04乾燥，過濾並真空濃縮。令殘 渣經矽膠管柱色析（梯度：0-30% EtOAc/己烷）純化，生成標 題化合物。MS(ESI，neg. ion·) m/z: 174 (M_l) 〇 Λ02 (b) l，5-二氟基-3-甲氧基-2-硝基苯。將碘化甲烷（4.36 mL， 70 mmol，Aldrich)加入得自上述步驟（a)之3,5-二氟基-2-石肖 基紛（7.18 g，41.1 mmol)與 K2C〇3(8.52 g，61.7 mmol，Aldrich) 之DMF(30mL)混合物。於室溫攪拌18h後，以H20稀釋該混 合物，並經Et20萃取（2x)。令合併之有機物經Na2S04乾燥， 過濾並減壓蒸發。令殘渣真空乾燥而生成標題化合物。 99461.doc -79-OH Λ02 (a) 3,5-difluoro-2-nitrophenol. 10N NaOH (12 mL, 120 mmol, JT Baker) was added to a solution of 1,3,5-trifluoro-2-nitrobenzene (10 g, 5.6 mmol, Aldrich) in DMSO (50 mL) and the mixture was taken to room Stir for 20h. The reaction mixture was diluted with H20 and extracted with EtOAc. The aqueous layer was separated and acidified to pH 5 with concentrated HCl and extracted with Et20 (2x). The combined organic extracts were washed with brine, dried EtOAc EtOAc The residue was purified by column chromatography (gradient: 0-30%EtOAc/hexanes) to afford title compound. MS (ESI, neg. ion·) m/z: 174 (M-1) 〇 Λ 02 (b) l, 5-difluoro-3-methoxy-2-nitrobenzene. Methane iodide (4.36 mL, 70 mmol, Aldrich) was added from the above step (a) 3,5-difluoro-2-zeschyl (7.18 g, 41.1 mmol) and K2C〇3 (8.52 g, 61.7 Mixture of DMF (30 mL) of mmol, Aldrich). After stirring at room temperature for 18 h, the mixture was diluted with H.sub.2 and extracted with Et20 (2x). The combined organics were dried over Na2SO4, filtered and evaporated. The residue was dried in vacuo to give the title compound. 99461.doc -79-

、0 、01295670, 0, 01295670

(c)N-(2,4-二甲氧芊基）-5 -氟基-3 -甲氧基_2_硝基苯胺。令得 自上述步驟（b)之1，5-二氟基-3 -甲氧基-2-硝基苯（4.00 g， 21·2 mmol)、2，4-二甲氧基苄胺（3.18 mL，21 ·2 mmol，Aldrich) 與三乙胺（2.96 mL，21.2 mmol)之 THF(210 mL)混合物於 7〇 C加熱20h。令反應混合物冷卻至室溫並真空去除揮發物。 溶殘渣於CHAh，並通過矽膠片，經CH2C12溶離。減壓蒸 發CH/h溶液，並令殘渣真空乾燥，生成黃色固體之標題 化合物。MS(ESI，pos· ion.) m/z: 359 (M+23)。(c) N-(2,4-Dimethoxyindolyl)-5-fluoro-3-methoxy-2-nitroaniline. 1,5-Difluoro-3-methoxy-2-nitrobenzene (4.00 g, 21.2 mmol), 2,4-dimethoxybenzylamine (3.18) obtained from the above step (b) A mixture of THF (2 mL, EtOAc, EtOAc) (EtOAc) The reaction mixture was allowed to cool to room temperature and the volatiles were removed in vacuo. The residue was dissolved in CHAh and passed through a ruthenium film and dissolved in CH2C12. The CH/h solution was evaporated under reduced pressure and the residue was evaporated to dryness crystals MS (ESI, pos. ion.) m/z: 359 (M+23).

((1)^-(2,4-二甲氧芊基）-5-氟基-3-甲氧基苯-l，2-二胺。令得 自上述步驟（c)之N-(2,4-二甲氧苄基）_5_氟基-3-甲氧基-2_ 石肖基苯胺（5.40 g，16.1 mmol)、鐵粉（325 網目，4.32 g， 77·3 mmol，Aldrich)、NH4C1(1.19 g，22.5 mmol，Aldrich) 與濃HC1(4滴）之EtOH(100 mL)與H2O(20 mL)混合物攪拌加 熱至70°C達3h。令反應混合物達室溫並持續攪拌16h。令混 合物濾過Celite®片，並減壓蒸發濾液。令殘渣真空乾燥， 生成標題化合物。 99461.doc -80 - 1295670((1)^-(2,4-Dimethoxyindolyl)-5-fluoro-3-methoxybenzene-1,2-diamine. N-(2) obtained from the above step (c) , 4-dimethoxybenzyl)_5-fluoro-3-methoxy-2_shidocylaniline (5.40 g, 16.1 mmol), iron powder (325 mesh, 4.32 g, 77·3 mmol, Aldrich), NH4C1 ( 1.19 g, 22.5 mmol, Aldrich) Concentrated HC1 (4 drops) of EtOH (100 mL) and H.sub.2 (20 mL) mixture was stirred and heated to 70 ° C for 3 h. The reaction mixture was allowed to reach room temperature and stirring was continued for 16 h. The Celite® tablets were filtered and the filtrate evaporated <RTI ID=0.0>

(e)l (2,4 - 一甲氧+基）_3 -胺基-7_氟基·5-甲氧基π奎号琳 -2(1Η)·酮。令得自上述步驟（d)之Νι_(2,4-二甲氧苄基）·5_氟 基-3-甲氧基苯·ι，2·二胺（4.92 g，16·1 mmol)與2·乙氧基_2、 亞胺基乙酸乙酯（5.54 g，38.14 mmol，根據 J· Chem. Soc· Perkin· Trans· 1，1999, 1789製成）之EtOH(100 mL)混合物於 室溫攪拌18h。過濾該反應混合物，並以EtOH洗濾塊，並 真空乾燥而生成細緻白色粉末之標題化合物。MS(ESI，p〇s. ion·) m/z: 360 (M+1)。(e) l (2,4 -monomethoxy+yl)_3-amino-7-fluoro-5-methoxy π-quinone- 2 (1 fluorene) ketone. Νι_(2,4-Dimethoxybenzyl)·5-fluoro-3-methoxybenzene·ι,2·diamine (4.92 g, 16.1 mmol) obtained from the above step (d) Ethyl ethoxide, ethyl iminoacetate (5.54 g, 38.14 mmol, according to J. Chem. Soc. Perkin Trans. 1, 1999, 1789) EtOH (100 mL) mixture at room temperature Stir for 18 h. The reaction mixture was filtered and washed with EtOAc (EtOAc) MS (ESI, p〇s. ion·) m/z: 360 (M+1).

(f)3-胺基-7-氟基-5-甲氧基喹嘮啉-2(1H)-酮。令得自上述步 驟（e)之1-(2,4-二甲氧苄基）-3-胺基-7-氟基-5-甲氧基喹嘮啉 _2(1H)_酮（3.0 g，8.34 mmol)、苯甲脒（4 mL，Aldrich)與三 氟乙酸（60 mL，Aldrich)加熱至65°C達16h，然後為85°C達 5h。令該反應混合物冷卻至室溫，並減壓蒸發。令殘渣於 25% i-PrOH/CHCl3與飽和NaHC03之間進行區分。收集有機 層並蒸發，生成固體殘渣。過濾該水層，並以H2〇洗濾塊， 並真空乾燥。合併濾塊與固體殘渣，並由Me0H再結晶而生 成標題化合物。MS(ESI，pos· ion.) m/z: 210 (M+1)。 99461.doc -81- 1295670(f) 3-Amino-7-fluoro-5-methoxyquinoxaline-2(1H)-one. 1-(2,4-Dimethoxybenzyl)-3-amino-7-fluoro-5-methoxyquinoxaline-2(1H)-one (3.0) obtained from the above step (e) g, 8.34 mmol), benzamidine (4 mL, Aldrich) and trifluoroacetic acid (60 mL, Aldrich) were heated to 65 ° C for 16 h and then at 85 ° C for 5 h. The reaction mixture was allowed to cool to room temperature and evaporated under reduced pressure. The residue was distinguished between 25% i-PrOH/CHCl3 and saturated NaHC03. The organic layer was collected and evaporated to give a solid residue. The aqueous layer was filtered and the filter was washed with H.sub.2 and dried in vacuo. The filter cake and solid residue were combined and recrystallized from MeOH to give the title compound. MS (ESI, pos. ion.) m/z: 210 (M+1). 99461.doc -81- 1295670

(g)3·胺基-7-氟基-5-經基喧17亏琳- 2(111)-0¾氣漠酸鹽。令得自 上述步驟（f)之3-胺基-7-氟基-5-甲氧基喹呤啉-2(1H)-酮（2.0 g，9.56 mmol)與 BBr3(1.0M之 CH2CI2，58 mL，58 mmol)於 實例56(b)之條件下進行反應，生成標題化合物。MS(ESI， pos· ion.) m/z: 196 (M+1) 0(g) 3 · Amino-7-fluoro-5-yl via 喧 17 琳 - 2 (111)-03⁄4 gas desert acid salt. 3-Amino-7-fluoro-5-methoxyquinoxaline-2(1H)-one (2.0 g, 9.56 mmol) obtained from the above step (f) and BBr3 (1.0M CH2CI2, 58 The reaction was carried out under the conditions of Example 56 (b) to give the title compound. MS(ESI, pos. ion.) m/z: 196 (M+1) 0

(h)3-胺基-5-(6-氣基嘧啶-4-基氧基）-7-氟基喹嘮啉-2(1H)-酮。令得自上述步驟（g)之3-胺基-7-氟基-5-羥基喹呤啉 -2(1H)-酮氫漠酸鹽（390 mg，2.0 mmol)與4，6-二氣基癌咬 (298 mg，2.0 mmol，Lancaster)於實例 26(a)之條件下進行 反應，生成標題化合物。MS(ESI，pos. ion·) m/z: 308 (M+1)。(h) 3-Amino-5-(6-oxapyrimidin-4-yloxy)-7-fluoroquinoxaline-2(1H)-one. 3-Amino-7-fluoro-5-hydroxyquinoxaline-2(1H)-one hydrogen oxalate (390 mg, 2.0 mmol) obtained from the above step (g) and 4,6-diox The base cancer bite (298 mg, 2.0 mmol, Lancaster) was reacted under the conditions of Example 26 (a) to give the title compound. MS (ESI, pos. ion·) m/z: 308 (M+1).

(i)(R)-%胺基氣基_5_(6-(4_(l-(4-氟苯基）乙基）六氮口比呼 -1-基）嘧啶-4-基氧基）喹嘮啉_2(1ίί)-酮。令得自上述步驟（h) 之3-胺基-5-(6-氣基嘧啶-4-基氧基）-7-氟基喹嘮啉-2(1 H)- 99461.doc -82- 1295670 酮（200 mg，0.65 mmol)與實例 23(c)之（R)-l-(l-(4-氟苯基） 乙基）六氫井（135 mg，0·65 mmol)於實例26(b)之條件下進 行反應，生成標題化合物。MS(ESI，pos. iQn.) m/z: 480 (M+l)。Mp:315〇C。 實例58(i) (R)-% Amino-based gas group _5_(6-(4-(l-(4-fluorophenyl)ethyl)hexaazinyl-heptyl-1-ylpyrimidin-4-yloxy) Quinoxaline-2 (1ίί)-ketone. 3-Amino-5-(6-oxapyrimidin-4-yloxy)-7-fluoroquinoxaline-2(1H)-99461.doc-82- obtained from the above step (h) 1295670 Ketone (200 mg, 0.65 mmol) and Example 23(c) (R) 1-(1-(4-fluorophenyl)ethyl)hexahydro well (135 mg, 0·65 mmol) in Example 26 The reaction was carried out under the conditions of (b) to give the title compound. MS (ESI, pos. iQn.) m/z: 480 (M+l). Mp: 315 〇 C. Example 58

(S)-3-胺基-7-氟基-5-(6-(4-(1-(4-氟苯基）乙基）六氫吼畊-1-基）嘧啶-4-基氧基）喹嘮啉-2(1H)-酮。令得自實例57(h)之3-胺基-5-(6-氯基嘧啶-4-基氧基）-7-氟基喹噚啉-2(1H)-酮 (150 mg，0.49 mmol)與（S)-l-(l-(4-氟苯基）乙基）六氫吼畊 (101 mg，0.49 mmo卜根據實例27所述加以製備）於實例26(b) 之條件下進行反應，生成標題化合物。MS(ESI，pos. ion.) m/z: 480 (M+l) 〇 Mp:288〇C 0(S)-3-Amino-7-fluoro-5-(6-(4-(1-(4-fluorophenyl)ethyl)hexahydroindole-1-yl)pyrimidin-4-yloxy Base) quinoxaline-2(1H)-one. 3-Amino-5-(6-chloropyrimidin-4-yloxy)-7-fluoroquinoxaline-2(1H)-one from Example 57 (h) (150 mg, 0.49 mmol And (S)-l-(l-(4-fluorophenyl)ethyl)hexahydroquinone (101 mg, 0.49 mmo b prepared according to Example 27) was carried out under the conditions of Example 26 (b) The reaction produces the title compound. MS (ESI, pos. ion.) m/z: 480 (M+l) 〇 Mp:288〇C 0

實例59Example 59

(a)l-((3-氟基-2_硝基苯氧基）甲基）-4-甲氧基苯。將4-甲氧苄 醇（12 mL，96·2 mmol)於0°C攪拌下逐滴加入NaH(60%礦物 油分散液，4·0 g，100 mmol)之THF(200 mL)懸浮液。令該 混合物於室溫攪拌15 min，然後添加2,6-二氟基-硝基苯 (15.26 g，100 mmol，Aldrich)。將生成之紅色溶液擾拌加 99461.doc • 83 - 1295670 熱至65°C，並藉TLC偵測反應進行。令反應混合物冷卻至 室溫，並真空去除溶劑。溶殘渣於MeOH，蒸發至Si02上， 並以25%之EtOAc/己烷溶離過Si02塞子。減壓蒸發溶劑，生 成黃色非結晶固體之粗產物，其不經另外純化即直接用於 下一步驟。MS(ESI，neg· ion·) m/z: 274·1(Μ-1)。(a) 1-((3-Fluoro-2-nitrophenoxy)methyl)-4-methoxybenzene. Add 4-methoxybenzyl alcohol (12 mL, 96.2 mmol) to a suspension of NaH (60% mineral oil dispersion, 4·0 g, 100 mmol) in THF (200 mL). . The mixture was stirred at room temperature for 15 min then 2,6-difluoro-nitrobenzene (15.26 g, 100 mmol, Aldrich). The resulting red solution was scrambled and added to 99461.doc • 83 - 1295670 to 65 ° C and detected by TLC. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was taken up in MeOH, evaporated to EtOAc EtOAc. The solvent was evaporated under reduced pressure to give a crude material crystals crystals crystals crystals. MS (ESI, neg. ion) m/z: 274·1 (Μ-1).

(b)3-(4-甲氧苄氧基）-Ν-甲基-2-硝基苯胺。令得自上述步驟 (a)之1-((3·氟基-2-硝基苯氧基）甲基）-4-甲氧基苯（0.60 g， 2.16 mmol)與甲胺（2.0M 之 MeOH 溶液，3.3 mL，6·6 mmol， Aldrich)於140°C微波爐反應器加熱30 min。令反應混合物 冷卻至室溫，並減壓蒸發。殘渣真空乾燥而生成標題化合 物0 MS(ESI，pos. ion·) m/z: 289 (M+1) 〇(b) 3-(4-Methoxybenzyloxy)-indole-methyl-2-nitroaniline. 1-((3·Fluoro-2-nitrophenoxy)methyl)-4-methoxybenzene (0.60 g, 2.16 mmol) obtained from the above step (a) and methylamine (2.0M The MeOH solution, 3.3 mL, 6·6 mmol, Aldrich) was heated in a microwave oven at 140 ° C for 30 min. The reaction mixture was cooled to room temperature and evaporated under reduced pressure. The residue was dried in vacuo to give the title compound. MS (ESI, pos. ion·) m/z: 289 (M+1) 〇

OHOH

Η (c)2-胺基-3-(甲基胺基）酚。令得自上述（b)之3-(4-甲氧苄氧 基）-N-甲基-2-硝基苯胺（3.11 g，10.8 mmol)與 10% Pd/C(0.31 g， Aldrich)之 MeOH(50 mL)混合物於 H2 氣壓下 攪拌16h。令混合物濾過Celite®片，並減壓蒸發濾液而生成 B 標題化合物。 99461.doc -84- 1295670Η (c) 2-Amino-3-(methylamino)phenol. 3-(4-methoxybenzyloxy)-N-methyl-2-nitroaniline (3.11 g, 10.8 mmol) obtained from the above (b) and 10% Pd/C (0.31 g, Aldrich) The MeOH (50 mL) mixture was stirred at mp. The mixture was filtered through Celite® and the filtrate was evaporated in vacuo to yield title compound. 99461.doc -84- 1295670

(d)3-胺基-5-羥基-1-甲基喹嘮啉_2(1H)_酮。令得自上述步驟 (c)2·胺基-3-(甲基胺基）紛（934 mg，6·67 mmol)與2_乙氧基 -2-亞胺基乙酸乙酯（1.96 g，13.52 mmo卜根據J· chem. Soc. Perkin. Trans. 1，1999, 1789製成）於實例57(e)之條件下進行 反應，生成標題化合物。MS(ESI，pos· ion.)m/z: 192 (M+1)。(d) 3-Amino-5-hydroxy-1-methylquinoxaline-2(1H)-one. Obtained from the above step (c) 2 · Amino-3-(methylamino) (934 mg, 6.67 mmol) and ethyl 2-ethoxy-2-imidoacetate (1.96 g, 13.52 mmol was prepared according to J. Chem. Soc. Perkin. Trans. 1, 1999, 1789. The reaction was carried out under the conditions of Example 57 (e) to give the title compound. MS (ESI, pos. ion.) m/z: 192 (M+1).

(6)3-胺基_5-(6-氣基,唆-4_基氧基）-1_甲基喧5琳_2(111)-酮。令得自上述步驟（d)之3-胺基-5-羥基-1-甲基喧吟淋 -2(1H)-酮（191 mg，1.0 mmol)與 4,6-二氣基嘴唆（149 mg， 1.0 mmol，Aldrich)於實例26(a)之條件下進行反應，生成標 題化合物。MS(ESI，pos. ion·) m/z: 304 (M+1)。(6) 3-Amino-5-(6-carbyl, indol-4-yloxy)-1_methylindole-5-lin-2(111)-one. 3-Amino-5-hydroxy-1-methylindole-2(1H)-one (191 mg, 1.0 mmol) obtained from the above step (d) and 4,6-dipyrene (唆) 149 mg, 1.0 mmol, Aldrich. MS (ESI, pos. ion·) m/z: 304 (M+1).

(f)(R)-3-胺基- 5-(6-(4-(1-(4 -氣苯基）乙基）六氫a比ττ井-卜基）喊 唆-4-基氧基）-1-甲基喧&quot;7号琳-2(1Η)-酮。令得自上述步驟（e) 之3 -胺基- 5-(6 -氣基σ密咬-4 -基氧基）-1_甲基噎g ^_2(ih)-酮（100 mg，0.33 mmol)與實例 23(c)之（R)-l-(l-(4_ 氟苯基） 乙基）六氫吡畊（68 mg，0·33 mmol)於實例26(b)之條件下進 99461.doc -85- 1295670 行反應，生成標題化合物。MS(ESI，pos. ion·) m/z: 476 (M+l)。Mp:256〇C 0 實例60(f) (R)-3-Amino- 5-(6-(4-(1-(4-)-phenyl)ethyl)hexahydro-a ratio ττ--Buji) Base)-1-methyl 喧 &quot; No. 7 Lin-2 (1 Η)-ketone. 3 -Amino 5-(6-aza-based sigma-4-yloxy)-1-methyl 噎g ^ 2 (ih)-one (100 mg, 0.33) obtained from the above step (e) Ment) with the (R)-l-(l-(4-fluorophenyl)ethyl)hexahydropyridine (68 mg, 0.33 mmol) of Example 23(c) under the conditions of Example 26(b) 99461.doc -85- 1295670 The reaction was carried out to give the title compound. MS (ESI, pos. ion·) m/z: 476 (M+l). Mp: 256〇C 0 instance 60

(S)-3_胺基-5-(6-(4-(1-(4-氟苯基）乙基）六氫吼畊-1_基）嘧啶 -4-基氧基）-1-曱基喹呤啉-2(1H)-酮。令得自實例59(e)之3-胺基-5-(6-氣基嘧啶-4_基氧基）-1-甲基喹嘮啉-2(1H)-酮（80 mg，0.26 mmol)與（S)-l-(1-(4-氟苯基）乙基）六氫σ比畊（55 mg，0.26 mmol，根據實例27所述加以製備）於實例26(b)之 條件下進行反應，生成標題化合物。MS(ESI，pos. ion.) m/z: 476 (M+l) 〇 實例61(S)-3_Amino-5-(6-(4-(1-(4-fluorophenyl)ethyl)hexahydroindole-1-yl)pyrimidin-4-yloxy)-1- Mercaptoquinoxaline-2(1H)-one. 3-Amino-5-(6-oxapyrimidin-4-yloxy)-1-methylquinoxaline-2(1H)-one from Example 59(e) (80 mg, 0.26 mmol And (S)-l-(1-(4-fluorophenyl)ethyl)hexahydro-sigma ratio (55 mg, 0.26 mmol, prepared according to Example 27) under the conditions of Example 26 (b) The reaction is carried out to give the title compound. MS (ESI, pos. ion.) m/z: 476 (M+l) 实例 Example 61

(a)5-(6-氟基嘧啶-4-基氧基）喹啉-2(1H)-酮。令5-羥基-喹啉 -2(lH)-_(0.05 g，0.31 mmol，根據 Shono, T·，Matsumura，Y·， Kashimura，S·，J. Org. Chem. 1981，46, 3719所述製成）、4,6-二氟基σ密变（0.036 mL，0.3 1 mmol，ABCR)與碳酸铯（0.2 g， 0.62 mmol)之DMF(5 mL)混合物於25°C攪拌2h。令該反應混 合物經H20(25 mL)稀釋。過渡收集生成之灰白色沈殿，並 真空乾燥而生成標題化合物。MS(ESI，pos· ion.) m/z: 258 (M+l) 〇 99461.doc -86- 1295670(a) 5-(6-Fluoropyrimidin-4-yloxy)quinolin-2(1H)-one. 5-hydroxy-quinoline-2(lH)-_(0.05 g, 0.31 mmol, according to Shono, T., Matsumura, Y., Kashimura, S., J. Org. Chem. 1981, 46, 3719 A mixture of 4,6-difluoro sigma (0.036 mL, 0.31 mmol, ABCR) and EtOAc (0.2 g, 0.62 mmol) The reaction mixture was diluted with H20 (25 mL). The resulting grayish white slab was collected and dried under vacuum to give the title compound. MS (ESI, pos. ion.) m/z: 258 (M+l) 〇 99461.doc -86- 1295670

(b)5-(6-(4-( 1-(4-氟苯基）乙基）六氫σ比畊-丨_基）嘧啶基氧 基）喹啉-2(lH)-iig。令得自上述步驟（&amp;)之5_(6-氟基嘧啶-4_ 基氧基）喹啉-2(1H)·酮（〇·〇5 g，〇·ΐ9 mmol)與實例2(b)之 卜[(18，111)-1-(4-氟苯基）乙基]六氫吡畊（〇〇4§，〇19111111〇1) 於實例26(b)之條件下進行反應而生成標題化合物。(b) 5-(6-(4-(1-(4-Fluorophenyl)ethyl)hexahydro-sigma ratio tillricin-yl)pyrimidinyloxy)quinoline-2(lH)-iig. 5_(6-Fluoropyrimidin-4-yloxy)quinolin-2(1H)·one (〇·〇5 g, 〇·ΐ9 mmol) obtained from the above procedure (&amp;) and Example 2(b) [(18,111)-1-(4-fluorophenyl)ethyl]hexahydropyrazine (〇〇4§, 〇19111111〇1) was reacted under the conditions of Example 26(b) to produce a title. Compound.

Mp:242.2〇C。MS(ESI，pos. ion·) m/z: 446 (M+1)。 另外的實例 下列實例係根據製備實例61所述之一般方法，或其些微 修正’由不同的經基取代雙環雜環（根據WO 2004/014871 所述製成）、4,6_二氣基嘧啶（ABCR)與l-[(lS，lR)·l-(4-氟基-苯基）-乙基l·六氫tI比畊（實例2(b))所製成：Mp: 242.2 〇C. MS (ESI, pos. ion·) m/z: 446 (M+1). Additional Examples The following examples are based on the general procedure described in Preparation Example 61, or some minor modifications 'substituted bicyclic heterocycles (formed according to WO 2004/014871), 4,6-dioxapyrimidines, as defined by different trans groups. (ABCR) and l-[(lS,lR)·l-(4-fluoro-phenyl)-ethyll·hexahydro-tI ratio (Example 2(b)):

實例 結 構 熔點(°c) M.S.(ESI)m/z 62 148 464 (M+l) 63 217 435 (M+l) 99461.doc -87- 1295670 64 N^N 672 431 (Μ+1) 65 丫。Η Ν^Ν 228 446 (Μ+1) NHAc 實例66Example Structure Melting Point (°c) MS (ESI) m/z 62 148 464 (M+l) 63 217 435 (M+l) 99461.doc -87- 1295670 64 N^N 672 431 (Μ+1) 65 丫. Η Ν^Ν 228 446 (Μ+1) NHAc Example 66

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Ν-(4-(6·(4·(1-(4-氟苯基）乙基）六氫吼畊-1-基）嘧啶-4-基氧 基）苯并[d]-呤唑-2-基）乙醯胺。令4-(6-(4-(1-(4-氟苯基）乙基） 六氫吡畊-1-基）嘧啶-4-基氧基）苯并[d]噚唑-2-胺（0.06 g， 〇·14 mmol，實例63)與乙酸酐於實例1(b)之條件下進行反 應，生成所需產物。Mp:199.8°C °MS(ESI，pos. ion.) m/z: 477 (M+1)° 實例67 NHAcΝ-(4-(6·(4·(1-(4-fluorophenyl)ethyl)hexahydroindole-1-yl)pyrimidin-4-yloxy)benzo[d]-carbazole- 2-yl) acetamidine. 4-(6-(4-(1-(4-fluorophenyl)ethyl)hexahydropyrylene-1-yl)pyrimidin-4-yloxy)benzo[d]oxazol-2-amine (0.06 g, 〇·14 mmol, Example 63) was reacted with acetic anhydride under the conditions of Example 1 (b) to give the desired product. Mp: 199.8 ° C ° MS (ESI, pos. ion.) m/z: 477 (M+1) ° Example 67 NHAc

(a)N-(4-(6-氟基嘴咬-4-基氧基）苯并[d]嗟嗤-2-基）乙醯胺。 令N_(4-羥基苯并[d]噻唑-2-基）乙醯胺（〇·3 g，14 mm〇1，根 據WO 2003/099284所述方法製成）與4,6•二氟基·嘧啶（〇 17 mL，1.4 mmol ’ ABCR)之DMF(3 mL)溶液於25。(：攪拌 18h。 99461.doc -88- 1295670 令該反應混合物經H2O(20 mL)稀釋，並過濾收集生成之灰 白沈殿物，並真空乾燥而生成標題化合物。MS(ESI，pos· ion·) m/z: 305 (M+1) 〇(a) N-(4-(6-Fluorodentyl-4-yloxy)benzo[d]indol-2-yl)acetamide. Let N_(4-hydroxybenzo[d]thiazol-2-yl)acetamide (〇·3 g, 14 mm〇1, prepared according to the method described in WO 2003/099284) and 4,6•difluoro • A solution of pyrimidine (〇17 mL, 1.4 mmol 'ABCR) in DMF (3 mL) at 25. (: stirring for 18 h. 99461.doc -88 - 1295670 The reaction mixture was diluted with H.sub.2 (20 mL). m/z: 305 (M+1) 〇

(b)(3R)-l-(l-(4-氟苯基）乙基）-3-甲基六氫α比畊。標題化合 物係根據類似實例2(a)之方式由（S)-(+)-甲基六氫啦畊（0.5 g，5.0 mmol，Aldrich)製備並分離成非結晶固體。MS(ESI， pos· ion·) m/z: 223 (M+1) 0(b) (3R)-l-(l-(4-fluorophenyl)ethyl)-3-methylhexahydro-α ratio tillage. The title compound was prepared from (S)-(+)-methylhexahydro-plow (0.5 g, 5.0 mmol, Aldrich) and separated into a non-crystalline solid according to the procedure of Example 2 (a). MS (ESI, pos· ion·) m/z: 223 (M+1) 0

(c)N-(4-(6-((R)-4((R)-(l-(4-氟苯基）乙基）-2-甲基六氫处畊 -1-基）嘧啶-4-基氧基）苯并[d]噻唑-2-基）乙醯胺。令得自上 述步驟（b)之（3R)-l-(l-(4-氟苯基）乙基）-3·曱基六氫吨啡 (0.20g，0.90 mmol)與得自上述步驟（a)之N-(4-(6-氟基嘴咬 -4-基氧基）苯并[d]噻唑-2·基）乙醯胺（0.27 g，0.90 mmol， Albany Molecular)之 DMF(5 mL)混合物於 100°C 攪:拌 3h。令 該反應混合物達25°C，並經H2O(40 mL)稀釋。過濾收集生 成之淡橙色沈澱物，並溶於DCM(50 mL)。以H20洗該溶液 (2x)，經無水硫酸鈉乾燥、過濾並蒸發。令殘渣經矽膠管柱 色析（梯度：0-4% MeOH/DCM)純化，生成非鏡象異構物混合 物之產物。MS (ESI，pos· ion.) m/z: 507 (M+1)。該非鏡象異 99461.doc -89- 1295670 構物藉超臨界液體色析[35% EtOH(0.2%二乙基胺）]分離。 收集第一個部分並真空濃縮，而生成白色固體之標題化合 物。MS(ESI，p0S· i〇n·) m/z: 507 (m+1)。 實例68(c) N-(4-(6-((R)-4((R)-(l-(4-fluorophenyl)ethyl)-2-methylhexahydro-l-yl)pyrimidine 4--4-yloxy)benzo[d]thiazol-2-yl)acetamide. (3R)-l-(l-(4-fluorophenyl)ethyl) obtained from the above step (b) -3·decyl hexahydro tonol (0.20 g, 0.90 mmol) and N-(4-(6-fluoro-mouth -4-yloxy)benzo[d]thiazole obtained from the above step (a) -2·yl) Mixture of acetaminophen (0.27 g, 0.90 mmol, Albany Molecular) in DMF (5 mL) at 100 ° C: stir for 3 h. Let the reaction mixture reach 25 ° C and pass H2O (40 mL) Dilute the resulting pale orange precipitate and dissolve in DCM (50 mL). Wash the solution (2×) with H20, dry over anhydrous sodium sulfate, filtered and evaporated. Purification of 0-4% MeOH/DCM) gave the product of a mixture of non-images. MS (ESI, pos. ion.) m/z: 507 (M +1). The non-image-like 99461.doc-89 - 1295670 The structure was isolated by supercritical liquid chromatography [35% EtOAc (0.2% EtOAc)]. n·) m/z: 507 (m+1). Example 68

N-(4-(6-((R)_4-((S)-l-(4-氟苯基）乙基）-2_甲基六氫吼畊小 基）’咬基氧基）苯并[d]嗔σ坐-2-基）乙酿胺。此化合物係 由實例67(c)之非鏡象異構物混合物經超臨界液體色析 [35% EtOH(0.2%二乙基胺）]分離之第二個部分之白色固 體。MS(ESI，pos· ion·) m/z: 507 (M+1)。 實例69N-(4-(6-((R)_4-((S)-l-(4-fluorophenyl)ethyl)-2-methylhexahydroindole)) And [d] 嗔σ sit-2-yl) ethylamine. This compound was the white solid of the second portion separated from the non-image mixture of Example 67 (c) by supercritical liquid chromatography [35% EtOH (0.2% diethylamine)]. MS (ESI, pos· ion·) m/z: 507 (M+1). Example 69

(R)-N_(8-(6-(4-( 1 - (4_敗苯基）乙基）六氫®比p井-1_基）啸咬-4_ 基氧基）喹啉-2-基）乙醯胺。令實例23(d)之8-(6-{4-[(lR)-(4-氟基-苯基）-乙基]-六氫σ比p井-l-基}-喊唆·4-基氧基）-哇琳_2-基胺（0·05g，0·llmmol)與乙酸酐於實例l(b)之條件下進行 反應，生成標題化合物。Mp: 134°C。MS(ESI，pos. ion.) m/z: 487 (M+1)。 實例70 99461.doc -90- 1295670(R)-N_(8-(6-(4-(1 -(4-)phenyl)ethyl)hexahydro® ratio p- well-1_yl)-biting-4_yloxy)quinoline-2 -yl) acetamidine. Let 8-(6-{4-[(lR)-(4-fluoro-phenyl)-ethyl]-hexahydro-sigma ratio p-well-l-base}- shout 唆4 of Example 23(d) -Ketyl)-wowline-2-ylamine (0.55 g, 0.11 mmol) was reacted with acetic anhydride under the conditions of Example l (b) to give the title compound. Mp: 134 ° C. MS (ESI, pos. ion.) m/z: 487 (M+1). Example 70 99461.doc -90- 1295670

8-(6-(4-(1-(4-氟苯基）乙基）六氫°比畊-1·基）嘧啶-4-基氧基） 異喹啉。令實例33(a)之4-氟基-6-(4-( 1-(4-氟苯基）乙基）六氫 吡呼-1_基）嘧啶（0.05 g，0.17 mmol)、異喹啉醇（0.037 g， 〇·25 mmol，Monomer Chem，Inc·)與碳酸铯（〇·〇81 g，0.25 mmol)與DMSO(l mL)之混合物於lire微波爐合成器中加 熱0.5h。令該反應混合物冷卻至室溫，經H2O(30 mL)稀釋， 並經DCM(2x50 mL)萃取。令合併之有機萃取物經H20洗（2 x3 0 mL)，經Na2S〇4乾燥、過濾並真空濃縮。令殘渣經矽膠 管柱色析（梯度：〇-8 % MeOH/DCM)純化，生成白色固體之 標題化合物。Mp: 114°C °MS(ESI，pos. ion.) m/z: 430 (M+1)。 實例718-(6-(4-(1-(4-Fluorophenyl)ethyl)hexahydro-ratio-1 -yl)pyrimidin-4-yloxy)isoquinoline. 4-fluoro-6-(4-(1-(4-fluorophenyl)ethyl)hexahydropyridin-1-yl)pyrimidine (0.05 g, 0.17 mmol), iso-quinoline of Example 33(a) A mixture of porphyrin (0.037 g, 〇·25 mmol, Monomer Chem, Inc.) and cesium carbonate (〇·〇 81 g, 0.25 mmol) and DMSO (1 mL) was heated in a lire microwave synthesizer for 0.5 h. The reaction mixture was cooled to rt EtOAc (EtOAc)EtOAc. The combined organic extracts were washed with EtOAc (EtOAc) The residue was purified by EtOAc EtOAc (EtOAc:EtOAc) Mp: 114 ° C ° MS (ESI, pos. ion.) m/z: 430 (M+1). Example 71

(a)5·經基啥p亏淋-2(1H)_鋼。令5-氧基-111_喧'^号淋-2-銅、實 例 54(b)(0.3 g，1.7 mmol)與 A1C13(2.0 g，15.5 mmol，Aldrich) 於實例25(d)之條件下進行反應而生成棕色粉末之標題化合 物。MS(ESI，pos· ion.) m/z: 163 (M+1) 0(a) 5 · 啥 啥 p 淋 -2 -2 (1H) _ steel. Let 5-oxy-111_喧'^# lynate-2-copper, Example 54(b) (0.3 g, 1.7 mmol) and A1C13 (2.0 g, 15.5 mmol, Aldrich) under the conditions of Example 25(d) The reaction was carried out to give the title compound as a brown powder. MS (ESI, pos. ion.) m/z: 163 (M+1) 0

Ν^γ°Ν^γ°

N^N 〇)5-(6_(4-(1-(4-氟苯基）乙基）六氫11比_-1-基）喊。定-4-基氧 99461.doc 〇i 1295670 基）喹啉-2(1H)-酮。令實例33(a)之4-氟基-6-(4-(1-(4-氟苯基） 乙基）六氫°比_-1-基）嘴咬（〇·4 g，1.3 mmol)與得自上述步驟 (a)之5-羥基喹噚啉-2(1 H)-酮（0.24 g，1.5 mmol)於實例70之 條件下進行反應而生成〇· 121 g(21%)淡黃色固體之標題化 合物。Mp:263 C。MS(ESI，pos. ion.) m/z: 447 (M+1)。N^N 〇) 5-(6-(4-(1-(4-fluorophenyl)ethyl)hexahydro-11- -1--1-yl) shouting. -4-yloxy 99461.doc 〇i 1295670 Quinoline-2(1H)-one. Example 34(a) 4-fluoro-6-(4-(1-(4-fluorophenyl)ethyl)hexahydropyrene--1-yl) mouth bite (〇·4 g, 1.3 mmol) And reacting with 5-hydroxyquinoxaline-2(1 H)-one (0.24 g, 1.5 mmol) from the above step (a) under the conditions of Example 70 to give 〇· 121 g (21%) The title compound of the yellow solid. Mp: 263 C. MS (ESI, pos. ion.) m/z: 447 (M+1).

(c)5-(6-(4-(l-(4-氟苯基）乙基）六氫σ比〃井-i-基）哺咬_4_基氧 基）-3,4-^一經基啥亏淋·2(1Η)_嗣。令得自上述步驟（b)之 5-(6-(4_(1-(4-氣苯基）乙基）六氫11比_-1-基）,唆—4-基氧基） 喹啉-2(1H)-酮（0.04 g，0.09 mmol)與 NaBH4(0.014 g，0.36 mmol，Aldrich)之 EtOH(2 mL)混合物於 25°C 攪拌 19h。令該 反應混合物經飽和碳酸氫鈉（25 mL)稀釋，並經DCM萃取（3 x25 mL)。令合併之有機萃取物經h2〇洗（25 mL)，經Na2S04 乾燥、過濾並真空蒸發。令殘渣懸浮於MeOH並過遽。分開 濾塊並真空乾燥，而生成灰白色固體之標題化合物。Mp:221 〇C 0 MS(ESI，pos· ion·) m/z: 449 (M+1)。 實例72(c) 5-(6-(4-(l-(4-fluorophenyl)ethyl)hexahydro-sigma ratio 〃井-i-yl)) _4_yloxy)-3,4-^ Once the basis of the loss of the rain · 2 (1 Η) _ 嗣. 5-(6-(4-(1-(4-Phenylphenyl)ethyl)hexahydro-11--1-yl), indole-4-yloxy)quinoline obtained from the above step (b) A mixture of -2(1H)-one (0.04 g, 0.09 mmol), EtOAc (EtOAc) The reaction mixture was diluted with saturated sodium bicarbonate (25 mL). The combined organic extracts were washed with EtOAc (EtOAc)EtOAc. The residue was suspended in MeOH and passed over. The filter cake was separated and dried in vacuo to give the title compound as a white solid. Mp: 221 〇C 0 MS (ESI, pos· ion·) m/z: 449 (M+1). Example 72

5-(6-(4-(1_(4·氟苯基）乙基）六氫a比畊-1_基）鳴咬·‘基氧基) 異喹啉-1(2H)-酮。令實例33(a)之4-氟基-6-(4-(1-(4·氟苯基〕 99461.doc -92- 1295670 乙基）六氫吡畊-1-基）嘧啶（0.074 g，0.24 mmol)與1,5-異喹 琳二醇（0.058 g，0.36 mmol，Sigma)於實例70之條件下進行 反應而生成標題化合物。Mp:249°C。MS(ESI，pos. ion.) m/z: 446 (M+l)。 實例735-(6-(4-(1_(4.fluorophenyl)ethyl)hexahydroa-ratio-1_yl), biting, &apos;-oxy group, isoquinoline-1(2H)-one. 4-fluoro-6-(4-(1-(4.fluorophenyl) 99461.doc -92- 1295670 ethyl)hexahydropyrylene-1-yl)pyrimidine of Example 33(a) (0.074 g) , 0.24 mmol) was reacted with 1,5-isoquinolinediol (0.058 g, 0.36 mmol, Sigma) under the conditions of Example 70 to give the title compound. Mp: 249 ° C. MS (ESI, pos. ion. m/z: 446 (M+l). Example 73

4-(6-(4-(l-(4_氟苯基）乙基）六氫啦畊-1-基）嘧啶-4-基氧基） 苯并[d]-噻唑-2-胺。令4-氟基-6-(4-(1-(4-氟苯基）乙基）六 氫吡畊-1-基）嘧啶（0.145 g，0.48 mmol，實例37(a))與2-胺 基·苯并噻唑 _4_醇（0.13 g，0·78 mmol，CarboGen)於實例 26(b) 之條件下進行反應，生成白色固體之標題化合物。Mp:222 〇C。MS(ESI，pos· ion·) m/z: 451 (M+1) 〇 實例744-(6-(4-(l-(4-Fluorophenyl)ethyl)hexahydro-peng-1-ylpyrimidin-4-yloxy)benzo[d]-thiazol-2-amine. 4-Fluoro-6-(4-(1-(4-fluorophenyl)ethyl)hexahydropyrrol-1-yl)pyrimidine (0.145 g, 0.48 mmol, Example 37(a)) and 2- The amine benzothiazole 4-alcohol (0.13 g, 0. 78 mmol, CarboGen) was taken to give the title compound as a white solid. Mp: 222 〇C. MS (ESI, pos· ion·) m/z: 451 (M+1) 实例 Example 74

(a)5-(6-氟基嘧啶-4-基氧基）-3,4-二氫喹啉-2(1H)-酮。標題 化合物係由5-羥基-3,4-二氫喹啉-2(111)-酮（0.18，0.61 mmol，根據 Shono，T·，Matsumura，Y·，Kashimura，S·，J· Org. Chem. 1981，46，3719所述製成）與 4,6-二氟基嘧啶（0.072 mL，0.62 mmol)於實例61(b)下之條件進行反應，生成標題 化合物0 MS(ESI，pos. ion·) m/z: 260 (M+1) 〇 99461.doc -93· 1295670(a) 5-(6-Fluoropyrimidin-4-yloxy)-3,4-dihydroquinolin-2(1H)-one. The title compound is from 5-hydroxy-3,4-dihydroquinolin-2(111)-one (0.18, 0.61 mmol, according to Shono, T., Matsumura, Y., Kashimura, S., J. Org. Chem. Prepared as described in 1981, 46, 3719) and 4,6-difluoropyrimidine (0.072 mL, 0.62 mmol). ·) m/z: 260 (M+1) 〇99461.doc -93· 1295670

(b)5-(6-(4-(l-(4·氣苯基）乙基）六氣0比喷-1·基）0¾唆_4_基乳 基）-3,4-二氫喹啉_2(1H)_酮。令得自上述步驟（a)之5-(6-氟 基嘧啶·4·基氧基）-3,4-二氫喹啉-2(1H)-酮（0.075 g，0.29 mmol)與實例2(b)之1-[(1S，1R)-1_(4-氟基-苯基）乙基]六氫 吡畊（0.04 g，0.19 mmol)於實例26(b)之條件下進行反應而 生成標題化合物。MS(ESI，pos. ion·) m/z: 448 (M+1)。 辣椒素誘導的原始背根神經結神經元之Ca2 +流入 將19天（E19)大的胚胎背根神經元（DRG)由定懷孕時間、末 期麻醉的 Sprague-Dawley 大鼠切出（Charles River, Wil mington，ΜΑ)並收集在包含5%熱抑制的馬jk清（Life Technologies, Grand Island，NY)之冰冷的 L_ 15培養基。然後 利用木瓜酶解離系統讓DRG解離成單一細胞懸浮液 (Worthington Biochemical Corp·，Freehold，NJ)。令解離的 細胞以200xg離心五分鐘形成凝塊，並再懸浮於包含1 mg/mL卵黏蛋白抑制劑、1 mg/mL卵白蛋白與0.005% DNase 之EB S S。令細胞懸浮液經由含10 mg/mL卵黏蛋白抑制劑、 10 mg/mL卵白蛋白之梯度溶液以200xg離心6分鐘去除細胞 碎片，並過滤過 88-μιη的尼龍網（Fisher Scientific，Pittsburgh， PA)而去除任何凝塊。利用血液細胞計數器決定細胞數量， 並以10 X 103細胞/槽將細胞接種在多鳥胺酸100 pg/mL(Sigma)與小鼠層枯連蛋白1 pg/mL(Life 99461.doc -94-(b) 5-(6-(4-(l-(4·Phenylphenyl)ethyl)hexafluoro 0-spray-1·yl)03⁄4唆_4_yl lactyl)-3,4-dihydrogen Quinoline-2(1H)-one. 5-(6-Fluoropyrimidin-4-yloxy)-3,4-dihydroquinolin-2(1H)-one (0.075 g, 0.29 mmol) from the above step (a) and Example 2 (b) 1-[(1S,1R)-1_(4-Fluoro-phenyl)ethyl]hexahydropyridine (0.04 g, 0.19 mmol) was reacted under the conditions of Example 26 (b) to give Title compound. MS (ESI, pos. ion·) m/z: 448 (M+1). Capsaicin-induced Ca2+ influx in primitive dorsal root ganglion neurons. 19-day (E19) large embryonic dorsal root neurons (DRG) were excised from Sprague-Dawley rats anesthetized at the end of pregnancy and at the end of anesthesia (Charles River, Wil mington, ΜΑ) and collected in ice-cold L-15 medium containing 5% heat-suppressed horse jk clear (Life Technologies, Grand Island, NY). The DRG was then dissociated into a single cell suspension using a papain dissociation system (Worthington Biochemical Corp., Freehold, NJ). The dissociated cells were centrifuged at 200 xg for five minutes to form a clot and resuspended in EB S S containing 1 mg/mL egg mucin inhibitor, 1 mg/mL ovalbumin and 0.005% DNase. Cell suspension was removed by centrifugation of the cell suspension through a gradient solution containing 10 mg/mL egg yolk inhibitor, 10 mg/mL ovalbumin at 200 xg for 6 minutes, and filtered through a 88-μηη nylon mesh (Fisher Scientific, Pittsburgh, PA) ) to remove any clots. The number of cells was determined using a blood cell counter, and cells were seeded at 10 x 103 cells/well in polyornosine 100 pg/mL (Sigma) and mouse laminin 1 pg/mL (Life 99461.doc -94-

12956701295670

Technologies)-塗覆的96槽培養盤之完全培養基。完全培養 基包含1··1之最低必須的培養基（MEN)與Ham’s F12、青黴素 (100 U/mL)與鏈黴素（100 pg/mL)與神經生長因子 (10ng/mL)、10%熱抑制的馬血清（Life Technologies)。將該 培養液保溫在37°C、5%C02與100%濕度。為控制非神經元 細胞的生長，我們在培養基中添加5 -氟基-21·去氧基尿癌淀 (75 μΜ)與尿嘧啶（180 μΜ)。VR1的活化是利用辣椒素刺激 (由0.01至10 μΜ)或藉酸刺激（添加緩衝為pH 4.1的30mM Hepes/Mes)達成。我們也在分析模式中測試化合物來評估 -它們對於VR1的激動劑性質。 辣椒素拮抗劑分析：將培養5天的E-19 DRG細胞與系列濃度 的VR1—起培育在37°C之HBSS(補充以BSA 0·1 mg/mL與1 111]^11邛63{117.4之1^111&lt;：8緩衝鹽液）15分鐘。然後於37°(：以 溶於包含 0·1 mg/mL BSA、15 mM Hepes pH 7.4 與 10 4〇^/1111/5€&amp;2+(八11^1811&amp;111)之1^111’8?12之活化緩衝劑的\/^1 激動劑_辣椒素200 nM，挑戰細胞2分鐘。 酸拮抗劑分析：在添加#5-45之30 mM Hepes/Mes緩衝液（終 分析pH5)之前先令化合物與E-19 DRG細胞預培育2分鐘， 然後再經另外2分鐘並將化合物洗出。終45 Ca(Amersham CES3-2mCi)為 10 pCi/mL。 激動劑分析：在化合物洗出之前令化合物在含弼-45的情形 下與 E-19 DRG 細胞培育 2 分鐘。終 45Ca2+(Amersham CES3-2mCi)為 10 pCi/mL。 化合物洗出與分析：在功能性分析後立即利用ELX405培養 99461.doc -95-Technologies) - Complete medium of coated 96-well plate. The complete medium contains the minimum necessary medium (MEN) of 1··1 with Ham's F12, penicillin (100 U/mL) and streptomycin (100 pg/mL) and nerve growth factor (10 ng/mL), 10% thermal inhibition Horse serum (Life Technologies). The culture was incubated at 37 ° C, 5% CO 2 and 100% humidity. To control the growth of non-neuronal cells, we added 5-fluoro-21-deoxyuridine (75 μΜ) and uracil (180 μΜ) to the medium. Activation of VR1 was achieved by capsaicin stimulation (from 0.01 to 10 μΜ) or by acid stimulation (addition of buffer to pH 4.1 of 30 mM Hepes/Mes). We also tested compounds in analytical models to assess their agonist properties for VR1. Capsaicin antagonist analysis: E-19 DRG cells cultured for 5 days were incubated with serial concentrations of VR1 at 37 °C in HBSS (supplemented with BSA 0·1 mg/mL and 1 111)^11邛63{117.4 1^111 &lt;:8 buffered saline) for 15 minutes. Then at 37° (: to dissolve in 1^111' containing 0·1 mg/mL BSA, 15 mM Hepes pH 7.4 and 10 4〇^/1111/5€&amp;2+(eight 11^1811&amp;111) 8/12 activation buffer \/^1 agonist _ capsaicin 200 nM, challenge cells for 2 minutes. Acid antagonist analysis: before adding #5-45 30 mM Hepes/Mes buffer (final analysis pH 5) The serotonin compound was pre-incubated with E-19 DRG cells for 2 minutes, and then the compound was washed out for an additional 2 minutes. The final 45 Ca (Amersham CES3-2mCi) was 10 pCi/mL. Agonist analysis: before the compound was washed out The compound was incubated with E-19 DRG cells for 2 minutes in the presence of sputum-45. The final 45Ca2+ (Amersham CES3-2mCi) was 10 pCi/mL. Compound washout and analysis: Immediately after functional analysis, EL461 was used to culture 99461. .doc -95-

1295670 盤清洗器（Bio-Tek Instruments Inc·)洗分析培養盤。以不含 Mg2+/Ca2+、含0· 1 mg/mL BSA之PBS洗3X 〇在每次清洗之 間擾動細胞。利用Micro Beta Jet(Wallac Inc.)讀取培養盤。 然後利用適當的計算系統來計算化合物活性。 45Ca2 +分析方法： 化合物可以採用於CMV啟動子下安定表現人類VR1或大鼠 VR1之Chinese Hamster Ovary細胞株來進行分析。可將細胞 培養於生長培養基，例行性地利用胰蛋白酶以70%覆蓋率 繼代，而且在進行化合物估計前24小時培養在分析培養盤。-可能的生長培養液： DMEM，高葡萄糖（Gibco 11965-084)。 10%透析過的血清（Hyclone SH3 0079.03)。 IX非必須胺基酸（Gibco 11140-050)。 IX 麵胺醯胺-Pen-Strep(Gibco 10378-016)。 G-418(Geneticin)，450 pg/mL(Gibco 10131-035)。 化合物可以利用100%DMSO稀釋，並利用數個對數單位的 濃度[40 μΜ-2ρΜ]測試其活性。在估計之前，化合物可以利 用HBSS緩衝液（pH 7.4)0.1 mg/mL BSA進行稀釋。在分析中 的DMSO終濃度為0.5%。每一個分析培養盤都僅可以利用 一種緩衝液與一種已知的拮抗劑化物進行控制（若非辣椒 氮呼（capsazepine)即是一種所述的VR1拮抗劑）。 VR1的活化可以利用辣椒素刺激（由0.1至1 μΜ)或藉酸刺 激（添加緩衝為ρΗ4· 1的30mM Hepes/Mes)達成。我們也可以 利用分析模式來測試化合物，以評估它們的VR1激動劑性 99461.doc -96- Γβ 1295670 質。 辣椒素拮抗劑分析：可以在添加弼-45與辣椒素之前讓化合 物與細胞預保溫兩分鐘（表現人類或大鼠VR1 )，然後在洗出 化合物之前讓它靜置另外兩分鐘。辣椒素（〇·5ηΜ)可以並用 HAM’s F12、0.1 mg/mL BSA、pH 7·4之 15mM Hepes來添加。 最終 45Ca(Amersham CES3-2mCi)為 10 pCi/mL。在人類 VR1 辣椒素拮抗劑分析中，下列化合物展現的IC50值低於 10mM 〇 2-((6-(4-((1 S)-1-(4-氟苯基）乙基）-1-六氫吼畊基）-4-嘧啶基）-氧基）喧琳； 2- 氣基-8_((6_(4_((lS)-l-(4-氟苯基）乙基）-1·六氫。比畊基）-4-嘧啶基）氧基）喹啉； 3- ((6-(4-((1 S)-1-(4-氟苯基）乙基）-1-六氫批畊基）-4_嘧啶基） 氧基）異喹啉； 3-胺基-5-((6-(4_((lR)·l-(4-氟苯基）乙基^l-六氫tϊ比p井基）-4-嘧啶基）氧基)-2(lH)-喹呤啉酮； 3-胺基-5-((6-(4-((lR)-l-(4-氟苯基）乙基）-1_六氫吼畊基）_4_ 嘧啶基）氧基）-1·曱基-2(1H)-喹嘮啉酮； 3-胺基-5-((6-(4-(( 1R)-1-(4-氟苯基）乙基）-1_六氫°比畊基）_4_ 嘧啶基）氧基）-1-甲基-2(1H)-喹嘮啉酮； 3-胺基-5-((6-(4-((1 S)-1-(4-氟苯基）乙基l·1·六氫ϋ比畊基）_4-嘧啶基）氧基）-2(1Η)-喹嘮啉酮； 3-胺基-5-((6-(4-((lS)-l-(4-氟苯基）乙基）_卜六氫°比畊基）-4_ 嘧啶基）氧基）-1-甲基-2(1H)-喹嘮啉酮； 99461.doc -97-1295670 Disk cleaner (Bio-Tek Instruments Inc.) washes the analysis plate. The cells were washed with PBS washed in PBS containing no Mg2+/Ca2+ and containing 0.1 mg/mL BSA, and the cells were perturbed between each wash. The plate was read using a Micro Beta Jet (Wallac Inc.). The compound activity is then calculated using an appropriate calculation system. 45Ca2+ analysis method: The compound can be analyzed by using the Chinese Hamster Ovary cell strain expressing human VR1 or rat VR1 under the CMV promoter. The cells can be cultured in growth medium, routinely passaged with trypsin at 70% coverage, and cultured in assay plates 24 hours prior to compound estimation. - Possible growth medium: DMEM, high glucose (Gibco 11965-084). 10% dialyzed serum (Hyclone SH3 0079.03). IX non-essential amino acid (Gibco 11140-050). IX Faceamine-Pen-Strep (Gibco 10378-016). G-418 (Geneticin), 450 pg/mL (Gibco 10131-035). Compounds can be diluted in 100% DMSO and tested for activity using several log units of concentration [40 μΜ-2ρΜ]. Compounds can be diluted with HBSS buffer (pH 7.4) 0.1 mg/mL BSA prior to estimation. The final concentration of DMSO in the assay was 0.5%. Each assay plate can only be controlled with a buffer and a known antagonist (if not capsazepine is one of the VR1 antagonists). Activation of VR1 can be achieved by capsaicin stimulation (from 0.1 to 1 μΜ) or by acid stimulation (addition of buffer to 30 mM Hepes/Mes of ρΗ4.1). We can also use analytical models to test compounds to assess their VR1 agonist properties 99461.doc -96- Γβ 1295670. Capsaicin Antagonist Analysis: Compounds can be pre-incubated with cells for two minutes (expressing human or rat VR1) prior to the addition of 弼-45 and capsaicin, and then allowed to stand for another two minutes before washing out the compound. Capsaicin (〇·5ηΜ) can be added in combination with HAM’s F12, 0.1 mg/mL BSA, and 15 mM Hepes at pH 7.4. The final 45Ca (Amersham CES3-2mCi) was 10 pCi/mL. In the human VR1 capsaicin antagonist assay, the following compounds exhibited IC50 values below 10 mM 〇2-((6-(4-((1))-1-(4-fluorophenyl)ethyl)-1-) Hexahydroindole)-4-pyrimidinyl)-oxy)anthracene; 2-alkyl-8_((6_(4_((lS)-l-(4-fluorophenyl)ethyl)-1) Hexahydro. Trargyl-4-pyrimidinyloxy)quinoline; 3-((6-(4-((1))-1-(4-fluorophenyl)ethyl)-1-6 Hydrogen-based cultivating)-4_pyrimidinyloxy)isoquinoline; 3-amino-5-((6-(4_((lR)·l-(4-fluorophenyl)ethyl)-l- Hexahydro-tϊ ratio p well base)-4-pyrimidinyloxy)-2(lH)-quinoxalinone; 3-amino-5-((6-(4-((lR)-l-( 4-fluorophenyl)ethyl)-1_hexahydroindolyl)_4_pyrimidinyloxy)-1·indolyl-2(1H)-quinoxalinone; 3-amino-5-(( 6-(4-((1R)-1-(4-fluorophenyl)ethyl)-1_hexahydro-ratio) _4_pyrimidinyloxy)-1-methyl-2(1H)- Quinoxalinone; 3-amino-5-((6-(4-((1))-1-(4-fluorophenyl)ethyl l·1·hexahydroindole) Ethyl)oxy)-2(1Η)-quinoxalinone; 3-amino-5-((6-(4-((lS)-l-(4-fluorophenyl)ethyl))) Hydrogen ratio phage base) -4_pyrimidinyloxy) -1-methyl-2(1H)-quinoxalinone; 99461.doc -97-

1295670 3-胺基-5-((6-(4-((18，1&amp;)-1-(4-敗苯基）乙基）-^六曼11比穿井 基）-4-嘧啶基）氧基）-2(1Η)-喹唠啉酮； 3-胺基-7-敗基-5_((6-(4-((1化)-1-(4_1苯基）乙基）_1_六氫11比 畊基）-4-嘧啶基）氧基）-2(1Η)-喹噚啉酮； 3-胺基_7·氟基-5-((6-(4-((lR)_l-(4-氟苯基）乙基）_1_六氫α比 畊基）-4-嘧啶基）氧基）-2(1Η)-喹嘮啉酮； 3- 胺基·7·1基-5-((6_(4-((lS)-l-(4-氟苯基）乙基六氫σ比 畊基）-4-嘧啶基）氧基）-2(1Η)-喹噚啉酮； &gt; 4-((6-(4-((lR)-1-(4-氟苯基）乙基）-1·六氫处啡基）-4-嘧啶基）- 氧基）喹啉； 4- ((6-(4-((11〇-1-(4-氟苯基）乙基）_1-六氫他畊基&gt;4-嘧啶基） 氧基）異喹啉； 4-((6_(4-((lR)-l-(4_氟苯基）乙基）-1_六氫吨畊基）-4-嘧啶基） 氧基）-1，3-苯并噻唑-2-胺； 4-((6_(4-((lS)-l-(4 -氟苯基）乙基）_1-六氫°比哨^基）_4_喊σ定基） 氧基）-1，3·二氫-2Η-苯并味σ坐-2-嗣； B 4-((6-(4-((1 S)-1-(4-氟苯基）乙基）-1-六氫啦畊基）_4·嘧啶基） 氧基）-2-甲基-1H-苯并咪唑； 4-((6-(4-((1 S)_l_(4-氟苯基）乙基）-1-六氫ϋ比畊基）_4·嘧唆基） 氧基）-1Η-吲哚； 4-((6-(4-(( 1S)-1-(4-氟苯基）乙基）-1-六氫σ比p井基）_4_喊啶基） 氧基）-1，3-苯并嘮唑-2-胺； 4-(2,3_ 二氫·1，4-苯并二呤畊 基氧基）-6-(4-((lS)-l-(4-氟 苯基）乙基）-1-六氫α比畊基）嘧啶； 99461.doc -98- 1295670 4- (2,3-二氫-苯并[1，4]二巧畊-5-基氧基）-6_{4_[l-(4-氟基- 苯基）-乙基]-六氫σ比呼-1_基}喊淀； 5_((6-(4-((1化)-1-(4-氟苯基）乙基）-1-六氫吨啡基）-4-嘧啶基） 氧基）-1，4-二氫-2,3-嗜ρ号淋二酮； 5- ((6-(4-((1 R)-l-(4-氟苯基）乙基）-1•六氫吨畊基）-4·嘧啶基） 氧基）異喹啉； 5-((6-(4-((1 R)-1-(4-氟苯基）乙基）-1-六氫^比呼基）·4_癌淀基） 氧基）喹琳； 丨 5-((6-(4-((1R)-1-(4-1苯基）乙基）-1-六鼠σ比呼基）-4-癌咬基）_ 氧基）-3,4-二氫-1(2H)-異喹啉酮； 5-((6-(4-((lR)-l-(4-氟苯基）乙基）_1_六氫ΰ比啩基）_4·嘧啶基） 氧基）-2(1Η)-喹啉酮； 5-((6-(4-(( 1R)-1-(4-氟苯基）乙基）-1-六氫吨畊基）-4-嘧啶基） 氧基）_3,4-二氫-2(1H)-喹啉酮； 5-((6-(4-((lS)-l_(4-氟苯基）乙基）_1_六氫吼畊基）-4-嘧啶基） 氧基）-1，3-二氫-2H-苯并咪唑-2-酮； ^ 5-((6-(4-((1 S)-1-(4-氟苯基）乙基）-1_六氫°比畊基）-4-嘧啶基） 氧基）·3,3·二甲基-1，3-二氫-2H-吲哚-2-酮； 5-((6-(4-((lS)-1-(4-氟苯基）乙基）-1-六氫σ比啡基）-4-嘧啶基） 氧基）-1，3-苯并噻唑-2-胺； 5-((6-(4-(( 1S)-1-(4-氟苯基）乙基）-卜六氫°比畊基）-4-嘧啶基） 氧基）-2(1Η)-喹哼啉酮； 5-((6-(4-((IS)-1-(4-氟苯基）乙基）-1_六氫u比畊基）-4-嘧啶基） 氧基）_3,4_二氫-2(1H)-喹嘮啉酮； 99461.doc •99- 1295670 5-((6-(4-((1 S)-l-(4-氟苯基）乙基）-1·六氫呢畊基）_4_嘧啶基） 氧基）-4a，8a-二氫喹嘮啉； 5- ((6-(4-((lS)-l-(4 -氟苯基）乙基）-1·六氲α比p井基）_4_嘴咬基） 氧基）-1(2Η)-異啥琳_ ; 6- ((6-(4-((lS)-l-(4-氟苯基）乙基）-1-六氫吨畊基）-4-嘧啶基） 氧基）-1Η_吲哚； 6-((6-(4-((1 S)-l_(4_氟苯基）乙基）-1-六氫吼畊基）-4-嘧啶基） 氧基）-2Η-1，4-笨并嘮畊-3(4H)-酮； 6-((6-(4-((1 S)-1-(4-氟苯基）乙基）-1·六氫处畊基）-4-嘧啶基） 氧基）異喹啉； 6-((6-(4-((1 S)-l_(4-氟苯基）乙基）·1-六氫吼畊基）-4-嘧啶基） 氧基）-3,4-二氫-2H-1，4-苯并嘮畊； 6- ((6-(4-(( lS)_l-(4 -敗苯基）乙基）-1-六氫11比啡基）_4_癌咬基） 氧基）啥琳； 7- ((6_(4_((lS)-1-(4-氟苯基）乙基）-1-六氫处畊基）_4_嘧啶基） 氧基）-1Η-吲哚； 7-((6-(4-((lS)-l-(4·氟苯基）乙基）-1-六氫η比畊基）_4_嘧啶基） 氧基）哇琳； 7-((6-(4-((lS)-l-(4-氟苯基）乙基）-1•六氫井基）_4_喊淀基） 氧基）異喹啉； 7- ((6-(4-((1 S)-l_(4-氟苯基）乙基）-1·六氫。比畊基）-4-嘧啶基） 氧基）-2-喹啉醇； 8- ((6_(4-((111)_1-(4-氟苯基）乙基）-1-六氫咬啡基兴4-嘧啶基） 氧基）-2-啥琳胺； 99461.doc -100-1295670 3-Amino-5-((6-(4-((18,1&amp;)-1-(4-phenylphenyl)ethyl)-^-hexan 11-pylinyl)-4-pyrimidinyl )oxy)-2(1Η)-quinoxalinone; 3-amino-7-f-yl-5-((6-(4-((1))-1-(4_1phenyl)ethyl))) _ hexahydro 11 ratio argonyl)-4-pyrimidinyloxy)-2(1Η)-quinoxalinone; 3-amino-7-fluoro--5-((6-(4-((lR) _l-(4-fluorophenyl)ethyl)_1_hexahydro-α ratio argonyl-4-pyrimidinyloxy)-2(1Η)-quinoxalinone; 3-amino-7·1 -5-((6-(4-((lS)-l-(4-fluorophenyl)ethylhexahydro-sigma))-pyridyl)-4-pyrimidinyloxy)-2(1Η)-quinoline 4-((6-(4-((lR)-1-(4-fluorophenyl)ethyl)-1·hexahydromorphinyl)-4-pyrimidinyl)-oxy) Quinoline; 4-((6-(4-((11〇-1-(4-fluorophenyl)ethyl))-hexahydro-t-heptin&gt;4-pyrimidinyl)oxy)isoquinoline; 4-((6-(4-((lR)-l-(4-fluorophenyl)ethyl)-1_hexahydro-tonyl)-4-pyrimidinyl)oxy)-1,3-benzoyl Thiazol-2-amine; 4-((6-(4-((lS)-l-(4-fluorophenyl)ethyl))-hexahydro-pyrene) _4_ _ σ 定 base) oxy) -1,3·Dihydro-2Η-benzo-flavor σ sitting-2-嗣; B 4-((6-(4- ((1 S)-1-(4-fluorophenyl)ethyl)-1-hexahydro-practinyl)_4·pyrimidinyloxy)-2-methyl-1H-benzimidazole; 4-( (6-(4-((1S)_l_(4-fluorophenyl)ethyl)-1-hexahydroindole) _ _4· pyridinyl) oxy)-1Η-吲哚; 4-( (6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-hexahydro σ ratio p well base) _4_ 啶 基) oxy)-1,3-benzo Oxazol-2-amine; 4-(2,3-dihydro-1,4-benzoindoleoxy)-6-(4-((lS)-l-(4-fluorophenyl)) ))-1-hexahydro-α ratio argon) pyrimidine; 99461.doc -98- 1295670 4- (2,3-dihydro-benzo[1,4] dioxin-5-yloxy)-6_ {4_[l-(4-Fluoro-phenyl)-ethyl]-hexahydro-sigma-1-}}}}}} -fluorophenyl)ethyl)-1-hexahydro-tonyl)-4-pyrimidinyloxy)-1,4-dihydro-2,3-isoprene-dione; 5- ((6) -(4-((1 R)-l-(4-fluorophenyl)ethyl)-1•hexahydro ton oleyl)-4·pyrimidinyloxy)isoquinoline; 5-((6- (4-((1 R)-1-(4-fluorophenyl)ethyl)-1-hexahydro^bendyl)·4_cancer) oxy)quinoline; 丨5-((6) -(4-((1R)-1-(4-1phenyl)ethyl)-1-hexameric σ 比 呼 )) -4-carcinoma) oxy)-3,4-dihydro-1(2H)-isoquinolinone; 5-((6-(4-((lR)-l-(4-fluorobenzene)) Ethyl)-1-hexahydroindole fluorenyl) _4. pyrimidinyl) oxy)-2(1Η)-quinolinone; 5-((6-(4-((1R)-1-)) -fluorophenyl)ethyl)-1-hexahydro ton oleyl)-4-pyrimidinyl)oxy)_3,4-dihydro-2(1H)-quinolinone; 5-((6-(4) -((lS)-l_(4-fluorophenyl)ethyl)_1_hexahydroindolyl)-4-pyrimidinyl)oxy)-1,3-dihydro-2H-benzimidazole-2- Ketone; ^ 5-((6-(4-((1))-1-(4-fluorophenyl)ethyl)-1_hexahydro-ratio)-4-pyrimidinyl)oxy) 3,3·dimethyl-1,3-dihydro-2H-indol-2-one; 5-((6-(4-((lS)-1-(4-fluorophenyl)ethyl)) -1-hexahydroσ-pyridyl)-4-pyrimidinyloxy)-1,3-benzothiazol-2-amine; 5-((6-(4-((1S)-1-)) -fluorophenyl)ethyl)- hexahydrogen ratio argonyl)-4-pyrimidinyloxy)-2(1Η)-quinoxalinone; 5-((6-(4-((IS)) -1-(4-fluorophenyl)ethyl)-1_hexahydrou-ratio argon-4-pyrimidinyloxy)_3,4-dihydro-2(1H)-quinoxalinone; 99461 .doc •99- 1295670 5-((6-(4-((1S)-l-(4-Fluorophenyl)ethyl)-1·hexahydro) _4_pyrimidinyl)oxy)-4a,8a-dihydroquinoxaline; 5-((6-(4-((lS)-l-(4-fluorophenyl)ethyl)-1·hexaquinone) α ratio p well base) _4_mouth bite base oxy)-1(2Η)-isoindene _ ; 6- ((6-(4-((lS)-l-(4-fluorophenyl)) ))-1-hexahydro ton oleyl)-4-pyrimidinyloxy)-1Η_吲哚; 6-((6-(4-((1))))) ))-1-hexahydroindole phenyl)-4-pyrimidinyl)oxy)-2Η-1,4- 唠 唠 -3-3(4H)-one; 6-((6-(4-(( 1 S)-1-(4-fluorophenyl)ethyl)-1·hexahydrocyl)-4-pyrimidinyloxy)isoquinoline; 6-((6-(4-((1) S)-l_(4-fluorophenyl)ethyl)·1-hexahydroindolyl)-4-pyrimidinyloxy)-3,4-dihydro-2H-1,4-benzopyrene 6-((6-(4-((lS)_l-(4--phenyl)ethyl)-1-hexahydro-l-l-yl)--4_carcinyl) oxy)啥; 7- ((6_(4_((lS)-1-(4-fluorophenyl)ethyl)-1-hexahydro) _4_pyrimidinyl)oxy)-1Η-吲哚; 7-((6 -(4-((lS)-l-(4.fluorophenyl)ethyl)-1-hexahydro-n-ratio) _4_pyrimidinyl)oxy)wowlin; 7-((6-(4) -((lS)-l-(4-fluorophenyl)ethyl)-1•hexahydrosolon)_4_叫) Oxy) isoquinoline; 7- ((6- (4 - ((1 S) -l_ (4- fluorophenyl) ethyl) -1-hexahydro.耕 ))-4-pyrimidinyl)oxy)-2-quinolinol; 8-((6-(4-((111)_1-(4-fluorophenyl)ethyl)-1-hexahydro) Morphnyl 4-pyrimidinyloxy)-2-indolylamine; 99461.doc -100-

1295670 8-((6-(4-((lR)-l-(4-氟苯基）乙基）·1-六氫&quot;比畊基）-4-嘧啶基） 氧基）-2-喹嘮啉胺； 8-((6-(4-((lR)· 1-(4-氟苯基）乙基）-1-六氫σ比咮基）-4-嘧啶基） 氧基）喹啉； 8-((6-(4-((lS)-l_(4_氟苯基）乙基）-1-六氫β比畊基）-4-嘧啶基） 氧基）-2-喹琳胺； 8-((6-(4-((1 S)-1-(4-氟苯基）乙基）-1-六氫°比畊基）-4-嘧啶基） 氧基）咪唑[l，2-a]吼啶； 8-((6_(4-((lS)-l-(4·氟苯基）乙基）-1_六氫11比畊基）-4-嘧啶基）-氧基）-1，4_二氫-3(2H)-異喹啉酮； 8-((6_(4-((lS)-l_(4-氟苯基）乙基）-1-六氫σ比畊基）-4_嘧啶基） 氧基）-2-唾4淋胺； 8-((6-(4-((IS)-1-(4-氟苯基）乙基）-1-六氫咐^井基）_4-嘧啶基） 氧基）異喹啉； N-(4-((6_((2R)_4-((lR)-l_(4·氟苯基）乙基）-2-甲基-1-六氫吨 畊基）-4-嘧啶基）氧基）-1，3-苯并噻唑-2-基）乙醯胺； N-(4-((6_((2R)_4-((lS)-l_(4-氟苯基）乙基）_2·甲基-卜六氫他 畊基）-4-嘧啶基）氧基）_1，3·苯并噻唑-2-基）乙醯胺； N-(4_((6-((2R)-4-((lS)-1-(4-氟苯基）乙基）-2-甲基 _1·六氫他 畊基）-4-嘧啶基）氧基）-1，3-苯并噻唑-2-基）乙醯胺； N-(4-((6_((2S)-4-((lS，lR)-l-(4_ 氟苯基）乙基）·2-甲基-1-六 氫°比畊基）-4-嘧啶基）氧基）-1，3-苯并噻唑-2-基）乙醯胺； 义(4-((6-((31〇-4-((111)_1-(4-氟苯基）乙基）-3-甲基-1-六氫°比 畊基）-4-嘧啶基）氧基）-1，3-苯并噻唑-2-基）乙醯胺； 99461.doc -101 -1295670 8-((6-(4-((lR)-l-(4-fluorophenyl)ethyl)·1-hexahydro&quot;specific argonyl)-4-pyrimidinyl)oxy)-2- Quinoxaline amine; 8-((6-(4-((lR)·1-(4-fluorophenyl)ethyl)-1-hexahydro-s-indolyl)-4-pyrimidinyl)oxy) Quinoline; 8-((6-(4-((lS)-l-(4-fluorophenyl)ethyl)-1-hexahydro-β-roughyl)-4-pyrimidinyl)oxy)-2- Quinolin; 8-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-hexahydro) arbutyl)-4-pyrimidinyloxy) Imidazole [l,2-a] acridine; 8-((6-(4-((lS)-l-(4.fluorophenyl)ethyl)-1_hexahydro-11) ()-oxy)-1,4-dihydro-3(2H)-isoquinolinone; 8-((6-(4-((lS))-l-(4-fluorophenyl)ethyl)-1 - hexahydro σ ratio cultivating base - 4 - pyrimidinyl) oxy) -2- stilbene; 8-((6-(4-((IS)-1-(4-fluorophenyl)ethyl) )-1-hexahydroanthracene)-4-pyrimidinyloxy)isoquinoline; N-(4-((6-((2R))4-((lR)-l_(4.fluorophenyl)) Ethyl)-2-methyl-1-hexahydro ton oleyl)-4-pyrimidinyloxy)-1,3-benzothiazol-2-yl)acetamide; N-(4-(( 6_((2R)_4-((lS)-l_(4-fluorophenyl)ethyl)_2·methyl-b hexahydro-tanning )-4-pyrimidinyloxy)_1,3·benzothiazol-2-yl)acetamidamine; N-(4-((6R)-4-((lS)-1-(4) -fluorophenyl)ethyl)-2-methyl_1·hexahydro-tallyl)-4-pyrimidinyloxy)-1,3-benzothiazol-2-yl)acetamide; N- (4-((6S((2S)-4-((lS,lR)-l-(4-fluorophenyl)ethyl)·2-methyl-1-hexahydro) (4-((6-((31)-1-(4-fluorophenyl))) Ethyl)-3-methyl-1-hexahydropyranyl)-4-pyrimidinyloxy)-1,3-benzothiazol-2-yl)acetamide; 99461.doc -101 -

1295670 N-(4-((6-((3R)_4-((lR)-l-(4-氟苯基）丙基）-3-甲基-1_ 六氫吼 畊基）-4-嘧啶基）氧基）-1，3-苯并噻唑-2-基）乙醯胺； N-(4_((6-((3R)-4-((lS)-l-(4-氟苯基）乙基）-3·甲基-1-六氫处 畊基）-4-嘧啶基）氧基）-1，3-苯并噻唑-2-基）乙醯胺； N-(4-((6-((3R)-4-((lS)-1-(4-氟苯基）丙基）-3-甲基-1-六氫吼 呼基）-4 -哺咬基）氧基）-1，3 -苯并嘆嗤-2-基）乙酿胺； N-(4-((6-(4-(lR)-l_(4-氟苯基）乙基）-1-六氫啦畊基）-4-嘧啶 基）氧基）-1，3-苯并噻唑-2-基）乙醯胺； &gt; N-(4-((6_(4-((lS)_l-(4·氟苯基）乙基）-1-六氫吼畊基）-4·嘧 _ 啶基）氧基）-1，3-苯并噻唑-2-基）乙醯胺； N-(4-((6-(4-((lS)_ 1-(4-氟苯基）乙基）-1-六氫0比畊基）-4-嘧 啶基）氧基）-1，3-苯并嘮唑-2-基）乙醯胺； N-(4_((6-(4-((lS，lR)-l-(2，4·二氟苯基）乙基）-1_六氫 ° 比口井 基）-4-嘧啶基）氧基）β1，3-苯并噻唑_2_基）乙醯胺； 1^-(4-((6_(4_((18，111)-1-(2-氟苯基）乙基）_卜六氫°比畊基）-4-Β 嘧啶基）氧基）-1，3-苯并噻唑-2-基）乙醯胺； &gt;1_(4-((6-(4-((18，111)_1-(2-吱喃基）乙基）-1-六氫°比11井基）-4-哺啶基）氧基）-1，3-苯并噻唑-2-基）乙醯胺； N-(4_((6-(4_((1S，1R)_i_(2_噻嗯基）乙基）-1-六氫°比畊基）-4-嘧啶基）氧基）-1，3-苯并噻唑_2_基）乙醯胺； N-(4-((6_(4-((lS，lR)-i-(3-氟苯基）乙基）-1-六氫。比畊基 M-嘧啶基）氧基）·1，3-苯并噻唑_2-基）乙醯胺； N-(4-((6-(4-((1S，1R)_i_(3_噻嗯基）乙基）-卜六氫 °比畊基）-4· 嘧啶基）氧基）-1，3-苯并噻唑_2_基）乙醯胺； 99461.doc -102-1295670 N-(4-((6-((3R))4-((lR)-l-(4-fluorophenyl)propyl)-3-methyl-1_hexahydroindole)-4-pyrimidine ))oxy)-1,3-benzothiazol-2-yl)acetamide; N-(4-((6-((3R)-4-((lS)-l-(4-fluorophenyl)) Ethyl)-3-methyl-1-hexahydro-practuring)-4-pyrimidinyloxy)-1,3-benzothiazol-2-yl)acetamide; N-(4-( (6-((3R)-4-((lS)-1-(4-fluorophenyl)propyl)-3-methyl-1-hexahydrofluorenyl)-4 -carto)oxy )-1,3-benzoxanthene-2-yl)ethinylamine; N-(4-((6-(4-(lR)-l-(4-fluorophenyl)ethyl)-1-) Hydrogenated benzylidene-4-pyrimidinyloxy)-1,3-benzothiazol-2-yl)acetamide; &gt; N-(4-((6_(4-((lS))) (4.Fluorophenyl)ethyl)-1-hexahydroindole cultivating base)-4-pyrimidinyloxy)-1,3-benzothiazol-2-yl)acetamide; N-( 4-((6-(4-((lS))-1-(4-fluorophenyl)ethyl)-1-hexahydro- 0-tough)-4-pyrimidinyloxy)-1,3- Benzooxazol-2-yl)acetamidamine; N-(4-((6-(4-((lS,lR)-l-(2,4.difluorophenyl)ethyl)-1_6) Hydrogen ° than the well base)-4-pyrimidinyloxy)β1,3-benzothiazol-2-yl)acetamide 1^-(4-((6_(4_((18,111)-1-(2-fluorophenyl)ethyl))- hexahydro-ratio)-4-indolepyrimidyl)oxy)- 1,3-benzothiazol-2-yl)acetamidamine; &gt;1_(4-((6-(4-((18,111))-1-(2-indolyl)ethyl)-1-) Hexahydrogen ratio 11 wells)-4-glycosyl)oxy)-1,3-benzothiazol-2-yl)acetamide; N-(4_((6-(4_((1S,1R) )_i_(2_Thienyl)ethyl)-1-hexahydrogen ratio argonyl)-4-pyrimidinyloxy)-1,3-benzothiazol-2-yl)acetamide; N- (4-((6-(4-((lS,lR)-i-(3-fluorophenyl)ethyl)-1-hexahydro). Till-based M-pyrimidinyloxy)·1,3- Benzothiazole-2-yl)acetamide; N-(4-((6-(4-((1S,1R)_i_(3_)))))) -4·pyrimidinyloxy)-1,3-benzothiazol-2-yl)acetamide; 99461.doc -102-

1295670 N_(4-((6-(4-((lS，lR)-l-(4·(甲氧基）苯基）乙基）-1-六氳 °比畊 基）_4_嘧啶基）氧基）-13-苯并噻唑·2-基）乙醯胺； n-(4-((6-(4-((1S，1R)-1-(4_(三氟甲基）苯基）乙基）-1-六氫啦 畊基）-4-嘧啶基）氧基）-i，3-苯并噻唑-2-基）乙醯胺； 义（4-((6-(4-((18，11〇-1-(4-溴苯基）乙基）-1-六氫吨_基）-4-嘧啶基）氧基）-1，3-苯并噻唑-2-基）乙醯胺； N_(4-((6-(4-((lS，lR)-1-(4-氯苯基）乙基）-1-六氫叱畊基）-4· 嘧啶基）氧基）-1，3-苯并噻唑-2-基）乙醯胺； N-(4-((6_(4-((lS，lR)· 1-(4-氟苯基）乙基）-1-六氫。比畊基）-4-嘧啶基）氧基）-1，3-苯并噻唑-2-基）乙醯胺； 1^(4-((6-(4-((18，111)_1-(4-氟苯基）丙基）-1-六氫吼畊基）-4-嘧啶基）氧基）-1,3-苯并噻唑-2-基）乙醯胺； N-(4-((6-(4_((lS，lR)-l_(4-e比受基）乙基）-1-六氮 °比 口井基）-4· 嘧啶基）氧基）-1，3-苯并噻唑-2_基）乙醯胺； N-(4-((6-(4-((lS，lR)-l-(5-溴基-2-噻嗯基）乙基）-1-六氫啦 畊基）-4-嘧啶基）氧基）-1，3-苯并噻唑-2-基）乙醯胺； N-(4_((6-(4-((lS，lR)-l_(5-氣基-2-噻嗯基）乙基）-1-六氫处 畊基）-4-嘧啶基）氧基）-1，3-苯并噻唑-2-基）乙醯胺；與 N-(8-((6-(4-((lR)-l_(4-氟苯基）乙基）_1_六氫。比畊基）-4-嘧 啶基）氧基）-2_喹啉基）乙醯胺； 酸拮抗劑分析：在添加溶於30 mM Hepes/Mes緩衝液之約 -45(終分析pH5)之前，可以先讓化合物與細胞（表現人類或 大鼠VR1者）預保溫兩分鐘，然後在洗出化合物之前令其再 經歷額外的兩分鐘。終45Ca(Amersham CES3-2 mCi)為10 99461.doc -103- 1295670 pCi/mL 〇 激動劑分析··在清洗化合物之前，可以讓化合物在含|弓 -45的條件下與細胞（表現人類或大鼠VR1者）培育兩分鐘。 終45Ca(Amersham CES3-2mCi)為 10 pCi/mL。1295670 N_(4-((6-(4-((lS,lR)-l-(4.(Methoxy)phenyl)ethyl)-1-hexafluoropyrene) _4_pyrimidinyl) Oxy)-13-benzothiazol-2-yl)acetamide; n-(4-((6-(4-((1S)))))) Ethyl)-1-hexahydrophosphonyl-4-pyrimidinyloxy)-i,3-benzothiazol-2-yl)acetamidamine; 4-((6-(4-) (18,11〇-1-(4-bromophenyl)ethyl)-1-hexahydrot-yl)-4-pyrimidinyloxy)-1,3-benzothiazol-2-yl) Indoleamine; N_(4-((6-(4-((lS,lR)-1-(4-chlorophenyl)ethyl)-1-hexahydroindole))-4-pyrimidinyloxy )-1,3-benzothiazol-2-yl)acetamide; N-(4-((6-(4-((lS,lR)· 1-(4-fluorophenyl)ethyl)-1) - hexahydro. 1,4- phenyl)-4-pyrimidinyloxy)-1,3-benzothiazol-2-yl)acetamide; 1^(4-((6-(4-((18, 111) 1 - (4-fluorophenyl) propyl)-1-hexahydroindole phenyl)-4-pyrimidinyloxy)-1,3-benzothiazol-2-yl)acetamide; N -(4-((6-(4-((()))))))))))))) 1,3-benzothiazol-2-yl)acetamide; N -(4-((6-(4-((lS,lR)-l-(5-bromo-2-yl)ethyl)-1-hexahydro]-pyrimidinyl)pyrimidinyl) Oxy)-1,3-benzothiazol-2-yl)acetamide; N-(4_((6-(4-((lS,lR)-l_(5-yl-2-yl) Ethyl)-1-hexahydro-hydrogenated 4-pyrimidinyloxy)-1,3-benzothiazol-2-yl)acetamide; and N-(8-((6-( 4-((lR)-l_(4-fluorophenyl)ethyl)_1_hexahydro. Specific cultivating)-4-pyrimidinyloxy)-2-quinolinyl)acetamide; acid antagonist Analysis: Compounds can be pre-incubated with cells (expressing human or rat VR1) for two minutes before adding the approximately -45 (final analysis pH 5) in 30 mM Hepes/Mes buffer, before eluting the compound. Let it go through an extra two minutes. The final 45Ca (Amersham CES3-2 mCi) is 10 99461.doc -103 - 1295670 pCi / mL 〇 agonist analysis · Before the compound is washed, the compound can be made in the containing - bow -45 The cells were incubated for two minutes with cells (expressing human or rat VR1). The final 45Ca (Amersham CES3-2mCi) was 10 pCi/mL.

化合物洗出與分析：在進行功能性分析之後立即利用 ELX405培養盤清洗器（Bio_Tek Instruments Inc.)清洗分析 培養盤。我們可以利用不含Mg2+/Ca2+、含(M mg/mL BSA 之PBS洗3 X，於清洗之間攪動細胞。培養盤可以利用 Mic^oBeta Jet(Wallac Inc.)讀取。然後可以利用適當的計算 糸統計算化合物的活性。 有用的核酸序列與蛋白質可以在美國專利號碼 6’335’180 ' 6,406,908與6,239,267發現，其全文並列於本文 供參考。 為了治療類香草精受體疾病諸如急性、發炎性與神 隻性疼痛、牙痛、一般性頭痛、偏頭痛、聚叢性頭痛、$ ^性血管與非血管症候群、緊張性頭痛、-般性發炎、！ 即人風濕病、骨關節炎、發炎性腸疾、發炎性眼疾、屬 炎性或不穩定性膀胱病症、牛皮癬、發炎性成分引起㈣ 膚不=H發X性病情、發炎性疼痛與相關的痛覺過每 與異m神經病變性疼痛與相關的痛覺過敏與異常病 痛糖尿病神經病變性疼痛、灼熱痛、交感神經所致的病 :神…症候群、氣喘、上皮細胞組織損害或功能 =早純泡療，，及道、泌尿生殖系統、胃腸或血管區 域的臟器蠕動失綱推 ，傷口、灼傷、過敏性皮膚反應、搐 99461.doc 1295670 療症、白耗、一般性胃腸病症、胃潰癌、十二指腸潰癌、 腹篇、致壞死劑造成的胃損傷、頭髮生長、血管運動或過 敏性鼻炎、支氣管病症或膀胱病症等人，本發明化合物= 採包含慣用的醫藥可接受之載體、佐劑與㈣之劑量單位 調配物而經口服、非經腸、#由吸人性噴霧、直腸或局部 施用。本文所用的&quot;非經腸&quot;術言吾包括皮下、靜脈内、肌内、 胸骨内、淨潤技術或腹膜内。Compound washout and analysis: Immediately after the functional analysis, the analytical plate was washed using an ELX405 plate washer (Bio_Tek Instruments Inc.). We can use a PBS containing no Mg2+/Ca2+ (M mg/mL BSA to wash 3X, stir the cells between washes. The culture plate can be read with Mic^oBeta Jet (Wallac Inc.). Then you can use the appropriate The calculation of the activity of the compound is calculated. Useful nucleic acid sequences and proteins can be found in U.S. Patent Nos. 6' 335 '180 ' 6, 406, 908 and 6, 239, 267, which are incorporated herein by reference in their entirety for the purposes of Sexual and divine pain, toothache, general headache, migraine, cluster headache, $ vascular and non-vascular syndrome, tension headache, general inflammation, ie rheumatism, osteoarthritis, inflammation Sexual bowel disease, inflammatory eye disease, inflammatory or unstable bladder disease, psoriasis, inflammatory components (4) skin not = H-like X-like condition, inflammatory pain and related painful per- and m-neuropathic pain Related hyperalgesia and abnormal pain Diabetic neuropathic pain, burning pain, sympathetic nerve disease: God... syndrome, asthma, epithelial tissue damage or function = early pure bubble Treatment,, and tract, genitourinary system, gastrointestinal or vascular area, organ peristalsis, wounds, burns, allergic skin reaction, 搐99461.doc 1295670 treatment, whiteness, general gastrointestinal disorders, gastric ulcer , duodenal ulcer, abdominal, gastric damage caused by necrotic agents, hair growth, vascular movement or allergic rhinitis, bronchial or bladder disorders, etc., the compound of the invention = contains a conventional pharmaceutically acceptable carrier, adjuvant Formulations with (4) dosage units are administered orally, parenterally, by inhalation spray, rectal or topical application. As used herein, &quot;parenteral&quot; is meant to include subcutaneous, intravenous, intramuscular, and sternal , net moist technology or intraperitoneal.

本文所述的疾病與病症之治療也想包括預防地施用本發 明化合物、-其醫藥上的鹽，或其醫藥組合物於我們認為^ 要對其進灯其例諸如疼痛、發炎與類似者之預防性治療的 病患（亦即動物’較佳者為哺乳類，又以人類最佳）。The treatment of the diseases and conditions described herein is also intended to include the prophylactic administration of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, which we believe to be illuminating, such as pain, inflammation, and the like. Patients with preventive treatment (ie, animals are preferably breast-feeding and human-optimal).

/用本發明化合物與/或本發明組合物而治療類香草精 又體媒&quot;的疾病’癌症與/或高▲糖症之劑量型式係根據多 種因素而定’包括疾病的型態、年齡、體重、性別、病患 的醫療情況、病情嚴重性、施用路徑與使用的特定化合物 等。因此’該劑量形式可能差異很大；但是，T以利用標 準方法例行性決定。劑量的範圍由約〇.(H mg〜3〇 mg公斤 重天車乂佳者為由約〇 lmg〜1〇mg/kg，更加者為由約m mg〜1 mg/kg，都適用於本文揭示的方法。 本I月的醫藥活性化合物可根據藥學上的慣用方法來加 而裝仏施用於包括人類與其他哺乳類之病患的藥劑。 供口服時，該醫荦扭人私π 梁、、且σ物可為例如膠囊、錠劑、懸浮液 或液體型式。該醫筚細人私 糸、、且D物較佳者係製成包含特定量之活 性成分的劑量單位型式。々 ^ 例如’這些可以包括的有效成分 99461.doc 1295670 的量為由約1〜2000 mg’較佳者為由卜5〇〇mg，更佳者為由 約5〜i50 mg。對於人類或其他哺乳類的適當日劑量而言’ 視病患的病情和其他因素而定差別可能很大；但是，再次 提醒此可利用例行性方法而決定。 人 該活性成分亦可藉由與包括鹽液、葡萄糖或水之適當栽 體做成之組合物注射施用。該每日的非經腸劑量型式：由 約0.1〜約30 mg/公斤總體重，較佳者為由約〇1〜約1〇 mg/kg ’更佳者為由約〇 25 mg〜1 mg/kg。 諸如無菌的注射水溶液或含油的懸浮液的注射用製劑， 可利用適當的分散或濕潤劑與懸浮劑根據已知方法調配。 該無菌注射用製劑亦可包含，例如1}3•丁二醇之無毒的非經 腸可接受的稀釋劑或溶劑，製成無菌注射用溶液或懸浮 液。可使用的可接受載劑與溶劑包括水、林格式液、等張 性氣化鈉溶液。此外，&amp;g的非揮發性油慣用做為溶液或 懸洋媒介。為此目的可使用任何溫和的非揮發性油，包括 合成的單-或雙甘油酯。此外，在製備注射製劑時也可使用 諸如油酸之脂肪酸。 藥物的直腸施用栓劑可藉混合該藥物與適當的非刺激性 賦形劑來製備’諸如可可脂與聚乙二醇之在常溫為固體， 但在直腸溫度為液體，並將因此在直腸溶解而釋放該藥物。 本發明之活性成分的適當局部劑量為0.lmg〜i5〇mg，每 天施用1到4次，較佳的為每天丨到2次。局部施用時，該活 性成分可能包括由0.001%〜10%重量/重量，例如調配物之 1%〜2〇/。重量；儘管，其可能包括多達1〇%重量/重量，但是 99461.doc •106· 1295670 較佳者為不大於5%重量/重量， q且更侄者為調配物之 〇·1 〜1% 〇 適於局部施用的調配物包括液體或半液體之適於穿透皮 膚的製劑（例如擦劑、乳液、油膏、乳霜或糊）與適於施用於 眼睛、耳朵或鼻子的滴劑。 施用時，通常將本發明化合物合併—或多種適於指示的 施用路徑之佐劑。該化合物可以混合乳糖、嚴糖、殿粉、 ㈣的纖維素酯類、硬脂酸、滑石、硬脂酸鎂、氧化鎂、 磷酸與硫酸的鈉與鈣鹽、阿拉伯膠、明膠、藻酸鈉、聚乙 醯比咯啶酮，與/或聚乙二醇並製成錠劑或包覆藥劑供傳統 施用。替代地，也可將本發明化合物溶解在食鹽、水、聚 乙二醇、丙二醇、乙醇、玉米油、花生油、棉籽油、芝麻 油、黃耆膠，與/或不同的緩衝液。其他的佐劑和作用模式 係醫藥技藝熟知者。載體或稀釋劑可能包括諸如單硬脂酸 甘油酯或雙硬脂酸甘油酯之單獨的時間延遲材料，或配人 • 臘或其他此技藝中熟知的材料。 該醫藥組合物可能製成固體型式（包括顆粒、粉末或拴劑） 或為液體型式（例如溶液、懸浮液或乳化液）。該醫藥組合2 可能進行諸如滅菌之慣用的醫藥操作，與/或可能包含諸如 防腐劑、安定劑、濕潤劑、乳化劑、緩衝劑等慣用的佐气。 口服施用的固體劑型可能包括膠囊、錠劑、藥丸、於末 與顆粒。在此類固體劑型中，該活性化合物可能混合至小 一種諸如蔗糖、乳糖或澱粉之惰性稀釋劑。此類劑型可能 亦如通常方法包括惰性稀釋劑以外的物質，例如諸如硬月匕 99461.doc -107- 1295670 酉文鎭之潤滑劑。在膠囊、鍵劑與藥丸的情形，該劑型可能 也包括緩衝劑。錠劑與藥丸可能另外與腸塗附物一起製備。 口服的液體劑型可能包括醫藥可接受的乳化液、溶液、 懸浮液、糖漿與包含諸如水之通常在此技藝使用的惰性稀 釋劑之酏劑。此類組合物可能也包括諸如濕潤劑、甜味劑、 調味劑與芳香劑之佐劑。 本發明化合物可以具有一或多個不對稱性碳原子，因此 _ 犯夠存在光學異構物形式，以及其消旋混合物或非消旋混 合物型式。該光學異構物可藉由根據慣用方法之解析消旋 混合物而取得，例如，藉由光活性酸或鹼之處理而形成非 鏡像異構物鹽類。適當的酸之實例為酒石酸、二乙醯基酒 石酸、二卞醯基酒石酸、二曱苯甲醯基酒石酸與樟腦磺酸， 然後藉由結晶，隨之為由這些鹽釋放光學活性的鹼，來分 離忒非鏡像異構物的混合物。有一種不同的分離光學異構 物的方法涉及使用最適當選擇之掌型色析管柱，以使對掌 ❿體的分離最大化。其他另外可使用的方法涉及藉由本發明 化合物與活化型 &lt; 之光學上純的酸，或是光學上純的異氮 酸鹽進行反應，合成共價的非鏡像異構物分子。該合成的 非鏡像異構物，可以藉諸如色層分析、蒸館、結晶或昇華 ^貫用方法加以分開，然後進行水解而產生對掌性純的化 、'物犬員此，本發明之光學活性化合物可藉用活性起始材 料而取得。這些異構物可為自由態酸、自由態驗、醋類或 鹽型式。 類此’本發明化合物可能存在異構物，亦即具相同分子 99461.doc 1295670 式，但是其中的原子相對於彼此為排列不㈤的化合物。特 別是本發明化合物的稀取代基，正常的而且較佳的是排列 並插入如這些基的個別定義所顯示的分子，而且是從左到 右讀取。然而，在某些情形下，熟諳此技藝者會了解可能 製作成其中廷些取代基相對於分子内的其他原子之方向是 相反的化合物。也就是說，除了它是以相反方向插入分子 以外，該要插入的取代基可能和上述者相同。熟諳此技藝 者會了解，本發明化合物的這些異構物形式，都應理解係 為本發明範疇所涵蓋。 本發明化合物可採用衍生自無機或有機酸的鹽型式。這 些鹽類包括但不限於下例者：乙酸鹽、己二酸鹽、藻酸鹽、 檸檬酸鹽、天冬胺酸鹽、苄酸鹽、苯磺酸鹽、亞硫酸鹽、 丁酸鹽、樟腦二酸鹽、樟腦磺酸鹽、二葡萄庚酸鹽、環物 烧丙酸鹽、十二烧硫酸鹽、乙烧續酸鹽、葡萄庚酸鹽、甘 油磷酸鹽、半硫酸鹽、庚酸鹽、己酸鹽、反丁烯二酸鹽、 氫氯酸鹽、氫溴酸鹽、氫碘酸鹽、2-羥基乙烷磺酸鹽、乳 酸鹽、順丁烯二酸鹽、甲烷磺酸鹽、菸鹼酸鹽、2_萘續酸 鹽、草酸鹽、雙羥萘酸鹽、果膠酸鹽、過硫酸鹽、孓苯基 丙酸鹽、苦味酸鹽、三甲基乙酸鹽、丙酸鹽、琥珀酸鹽、 酒石酸鹽、硫氰酸鹽、甲苯磺酸鹽、甲烷磺酸鹽與十一烧 酸鹽。而且鹼性的含氮基可以利用諸如下列者加以四級 化，諸如甲基、乙基、丙基與丁基之氣化物、溴化物與蛾 化物之低碳素烷基鹵化物，像是二甲基、二乙基、二丁基 與二戊基硫酸酯之硫酸二烷酯，諸如癸基、十二基、十四 99461.doc -109- 1295670 基與硬脂基氣化物、溴化物與碘化物之長鏈鹵化物，像是 +基與本乙基漠化物之芳烧基鹵化物和其他者。藉此可取 得水或油可溶或可分散的產物。 可能用來形成醫藥可接受的酸加成鹽的酸之實例包括， 諸如氫氣酸、硫酸與填酸之無機酸以及諸如草酸、順丁稀 二酸、琥珀酸與檸檬酸之有機酸。其他實例包括與鹼金屬 或鹼土金屬諸如鈉、鉀、鈣或鎂，或於有機鹼形成的鹽。 本發明範疇也包括羧酸或含羥基之醫藥可接受的酯，包 括本發明化合物之代謝不安定的酯或前藥型式。代謝不安 定的酯是可能產生例如，使該化合物的血含量增加並延長 對應的非酯化型式的化合物之效率。前藥型式係非以分子 的活性型式施用，但是經由諸如例如酶或水解切斷之代謝 作用之活體内的作用或生物轉型而成為具治療活性的型 式。對於涉及酯類之一般討論，請參照8¥61138011與TunekDosage of a disease-like cancer and/or high ▲ glycoside with a compound of the present invention and/or a composition of the present invention is based on a variety of factors, including the type and age of the disease. , weight, sex, medical condition of the patient, severity of the disease, route of administration and specific compounds used. Thus the dosage form may vary widely; however, T is routinely determined using standard methods. The dosage range is from about 〇. (H mg~3〇mg kg 车 乂 者 者 为 〇 mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg The disclosed pharmaceutically active compound can be applied to a patient including a human and other mammals according to a pharmaceutically acceptable method. When administered orally, the doctor twists the human π beam, And the σ substance may be, for example, a capsule, a lozenge, a suspension or a liquid type. The doctor's order is fine, and the D substance is preferably made into a dosage unit type containing a specific amount of the active ingredient. These may include the active ingredient 99461.doc 1295670 in an amount of from about 1 to 2000 mg' preferably from 5 〇〇 mg, more preferably from about 5 to 50 mg. Suitable days for humans or other mammals The dose may vary greatly depending on the condition of the patient and other factors; however, it is again reminded that this can be determined by routine methods. The active ingredient can also be used with and including saline, glucose or water. A composition prepared from a suitable carrier is administered by injection. The daily parenteral Dosage form: from about 0.1 to about 30 mg / kg total weight, preferably from about 1 to about 1 mg / kg 'better than about 25 mg ~ 1 mg / kg. Such as sterile injection The preparation for injection of an aqueous solution or an oil-containing suspension may be formulated according to known methods using a suitable dispersing or wetting agent and a suspending agent. The sterile injectable preparation may also contain, for example, a non-toxic non-toxic solution of 1}3 • butanediol. An enteric acceptable diluent or solvent is prepared as a sterile injectable solution or suspension. Acceptable carriers and solvents include water, forest format, isotonic sodium solution. In addition, &amp;g Volatile oils are conventionally used as solutions or suspension vehicles. Any mild, non-volatile oil may be employed for this purpose, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may also be used in the preparation of injectable preparations. Rectal administration of a drug can be prepared by mixing the drug with a suitable non-irritating excipient. 'Cocoa butter and polyethylene glycol are solid at room temperature, but liquid at the rectal temperature, and will therefore dissolve in the rectum. And release the drug. A suitable topical dose of the active ingredient of the present invention is 0.1 mg to 5 mg, administered 1 to 4 times a day, preferably 2 times a day. For topical application, the active ingredient may include from 0.001% to 10%. Weight/weight, for example, 1% to 2% by weight of the formulation; although it may include up to 1% by weight/weight, 99461.doc • 106· 1295670 is preferably not more than 5% by weight/weight , q and more 为1 to 1% of the formulation 〇 Suitable formulations for topical application include liquid or semi-liquid formulations suitable for penetrating the skin (eg, liniments, lotions, ointments, creams or Paste) with drops suitable for application to the eyes, ears or nose. When administered, the compounds of the invention are typically combined - or a plurality of adjuvants suitable for the indicated route of administration. The compound may be mixed with lactose, Yan sugar, house powder, cellulose ester of (4), stearic acid, talc, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric acid and sulfuric acid, gum arabic, gelatin, sodium alginate. , polyvinylpyrrolidone, and / or polyethylene glycol and made into tablets or coating agents for traditional application. Alternatively, the compounds of the invention may also be dissolved in salt, water, polyethylene glycol, propylene glycol, ethanol, corn oil, peanut oil, cottonseed oil, sesame oil, tragacanth, and/or different buffers. Other adjuvants and modes of action are well known to those skilled in the art. The carrier or diluent may include a separate time delay material such as glyceryl monostearate or glyceryl distearate, or may be formulated with a wax or other materials well known in the art. The pharmaceutical composition may be in a solid form (including granules, powders or elixirs) or in a liquid form (such as a solution, suspension or emulsion). The pharmaceutical combination 2 may be subjected to conventional medical procedures such as sterilization, and/or may contain conventional adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, buffers, and the like. Solid dosage forms for oral administration may include capsules, lozenges, pills, and granules. In such solid dosage forms, the active compound may be mixed in a small inert diluent such as sucrose, lactose or starch. Such dosage forms may also include materials other than inert diluents, such as, for example, a lubricant such as Hardy's 99461.doc -107-1295670. In the case of capsules, keys and pills, the dosage form may also include a buffer. Tablets and pills may additionally be prepared with the intestinal coating. Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents such as those normally employed in the art. Such compositions may also include adjuvants such as wetting agents, sweeteners, flavoring agents, and flavoring agents. The compounds of the invention may have one or more asymmetric carbon atoms and are therefore present in the form of optical isomers, as well as their racemic or non-racemic mixture forms. The optical isomer can be obtained by analysing the racemic mixture according to a conventional method, for example, by treatment with a photoactive acid or a base to form a non-image salt. Examples of suitable acids are tartaric acid, dimercapto tartaric acid, dimercapto tartaric acid, benzhydryl tartaric acid and camphorsulfonic acid, which are then separated by crystallization, followed by the release of an optically active base from these salts. A mixture of non-mirromeric isomers. A different method of separating optical isomers involves the use of the most appropriate palm-type chromatography column to maximize separation of the palms. Other methods which may be used involve the synthesis of covalent non-image material molecules by reaction of a compound of the invention with an activated &lt; optically pure acid or optically pure isocyanate. The synthesized non-image isomer can be separated by, for example, chromatography, steaming, crystallization or sublimation, and then hydrolyzed to produce pure palmization, 'the dog, this invention Optically active compounds can be obtained by borrowing an active starting material. These isomers can be free acid, free state, vinegar or salt form. The compound of the present invention may be present as an isomer, i.e., a compound having the same molecular formula 99461.doc 1295670, but in which the atoms are arranged in a non-(5) relationship with respect to each other. In particular, the dilute substituents of the compounds of the invention are normally and preferably arranged and inserted into the molecules as indicated by the individual definitions of these groups, and are read from left to right. However, in some instances, those skilled in the art will recognize compounds that may be made to have opposite substituents in the direction of other atoms in the molecule. That is, the substituent to be inserted may be the same as the above except that it is inserted in the opposite direction. It will be understood by those skilled in the art that these isomeric forms of the compounds of the invention are understood to be encompassed within the scope of the invention. The compounds of the invention may be in the form of a salt derived from an inorganic or organic acid. These salts include, but are not limited to, the following: acetate, adipate, alginate, citrate, aspartate, benzylate, besylate, sulfite, butyrate, Camphoric acid salt, camphor sulfonate, diheptinium heptanoate, cyclate propionate, twelfth sulphate, ethionate, grape heptanoate, glycerol phosphate, hemisulfate, heptanoic acid Salt, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethane sulfonate, lactate, maleate, methanesulfonic acid Salt, nicotinic acid salt, 2-naphthoate, oxalate, pamoate, pectate, persulfate, decyl propylate, picrate, trimethylacetate, Propionate, succinate, tartrate, thiocyanate, tosylate, methanesulfonate and undecanoate. Further, the basic nitrogen-containing group may be subjected to a quaternization such as a methyl group, an ethyl group, a propyl group and a butyl group, a bromide compound and a molybdenum lower carbon alkyl halide, such as two. Dialkyl sulfates of methyl, diethyl, dibutyl and dipentyl sulfate, such as decyl, dodecyl, tetradecyl 99461.doc -109-1295670 and stearyl vapors, bromide and A long chain halide of iodide, such as an aryl halide of the + group and the present ethyl desert, and others. Thereby, a water or oil soluble or dispersible product can be obtained. Examples of the acid which may be used to form a pharmaceutically acceptable acid addition salt include, for example, hydrogen acid, sulfuric acid and acid-filled inorganic acid, and organic acids such as oxalic acid, cis-succinic acid, succinic acid and citric acid. Other examples include salts with alkali or alkaline earth metals such as sodium, potassium, calcium or magnesium, or with organic bases. Also included within the scope of the invention are carboxylic acids or pharmaceutically acceptable esters containing hydroxyl groups, including metabolically unstable ester or prodrug forms of the compounds of the invention. A metabolically unstable ester is one that is likely to produce, for example, an increase in the blood content of the compound and an increase in the efficiency of the corresponding non-esterified version of the compound. The prodrug form is not administered in a molecularly active form, but is in a therapeutically active form via an in vivo action or biological transformation such as, for example, enzymatic or hydrolytical cleavage. For a general discussion of esters, please refer to 8¥61138011 and Tunek

Drug Metabolism Reviews 165(1988)以及 Bundgaard Design of Prodrugs，Elsevier(1985)。遮蔽的羧酸陰離子的實例包括 各種酯類’諸如烷基（例如，甲基、乙基）、環烷基（例如， 環己基），芳烷基（例如，苄基、對_甲氧芊基）與烷羰氧烷基 (例如，三甲基乙醯基氧甲基）。胺已經被遮蔽為芳基羰氧甲 基取代的衍生物，其在活體内會藉酯酶切段而釋放自由態 藥物與甲醛（Bundgaard J· Med· Chem· 2503(1989))。而且， 諸如。米。坐、亞醯胺、,σ朵與類似者之包含酸性nh基的藥 物’已經利用Ν·隨氧曱基來遮蔽（Bundgaard Design of Prodrugs，Elsevier(1985))。羥基經遮蔽為酯類與醚類。Ep 99461.doc -110- 1295670 039,05 l(Sloan 與 Little，4/11/81)揭示 Marmich鹼異羥肟酸前Drug Metabolism Reviews 165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985). Examples of masked carboxylic acid anions include various esters such as alkyl (e.g., methyl, ethyl), cycloalkyl (e.g., cyclohexyl), aralkyl (e.g., benzyl, p-methoxy) And an alkylcarbonyloxyalkyl group (for example, trimethylacetoxymethyl). The amine has been masked as an arylcarbonyloxymethyl-substituted derivative which releases a free state drug and formaldehyde by esterase cleavage in vivo (Bundgaard J. Med. Chem. 2503 (1989)). And, such as. Meter. Sodium, imipenem, σ, and the like, which contain an acidic nh group, have been masked with Ν· 曱 曱 (Bundgaard Design of Prodrugs, Elsevier (1985)). Hydroxyl groups are masked as esters and ethers. Ep 99461.doc -110- 1295670 039,05 l (Sloan and Little, 4/11/81) reveals the Marmich base before the hydroxamic acid

藥、其製法與用途。本發明化合物的酯類可能包括例如， 甲基、乙基、丙基與丁基酯，以及其他在酸性部分以含羥 基部分形成的適當酯類。代謝不安定的g旨類可能包括例 如，甲氧甲基'乙氧甲基、異丙氧甲基、心甲氧乙基，諸 如例如甲氧乙基、乙氧乙基、丙氧乙基、異丙氧乙基等等 之(X-UCVC4)烷氧基）乙基；諸如5_曱基_2_氧基_i，3_二啰戊 烯-4-基甲基等之2-氧基-M-二,号戊烯|基曱基；例如曱硫 曱基、乙硫甲基、異丙硫甲基等之Ci-C3烷硫甲基；例如三 甲基乙醯基氧甲基、α-乙醯氧甲基等之醯氧甲乙氧羰 基-1-曱基或例如乙醯氧乙基之心醯氧基_α•取代的甲基。 甚且，本發明化合物可能存在能經由諸如乙醇、ν，沁二 甲基甲醯胺、水或類似者之普通溶劑形成結晶之結晶固 體。因此’本發明化合物的結晶形式可能以親代化合物或 其醫藥可接受的鹽之同質異松种， 負吳14體，溶劑合物與/或水合物存 在。類此’所有此_式都應該理解係為本發明範脅所涵 儘管，本發明化合物可採單 它們也可合併一或多種本發明 做為合併物施用時，該治療藥 同時間施用的分別的組合物， 組合物施用。 獨的活性藥劑施用；然而， 化合物或其他藥劑使用。當 劑可调配成在相同時間或不 或該治療藥物可做為單一的 ★ ’〜刺询不的化合物 明。對於熟諳此技藝者报明顯 物· 刃差異與改變，都為在丨 9946l.doc -111. 1295670 的申請項中加以定義的本發明範疇與特性所涵蓋。 由前述說明，熟諳此技藝者很谷易確定本發明的必要特 徵；而且，不會偏離其精神與範 改變與修正，以使得它此夠適用 可即可對本發明做不同的 於不同的用途和條件。Medicine, its preparation and use. The esters of the compounds of the invention may include, for example, methyl, ethyl, propyl and butyl esters, as well as other suitable esters formed in the acidic moiety with a hydroxyl containing moiety. Metabolically unstable g-like classes may include, for example, methoxymethyl 'ethoxymethyl, isopropoxymethyl, cardiomethoxyethyl such as, for example, methoxyethyl, ethoxyethyl, propoxyethyl, (X-UCVC4)alkoxy)ethyl group such as 5-isopropyloxy-2-ethyl; a group of -M-di, pentene groups; a mercapto group; for example, a Ci-C3 alkylthiomethyl group such as anthracenethiomethyl, ethylthiomethyl, isopropylthiomethyl, etc.; for example, trimethylethenyloxymethyl And a methoxy-ethoxycarbonyl-1-indenyl group such as α-acetoxymethyl or a cardiooxy-α-substituted methyl group such as an ethoxylated ethyl group. Further, the compound of the present invention may have a crystalline solid which can be crystallized via a common solvent such as ethanol, ν, dimethyl dimethylformamide, water or the like. Thus, the crystalline form of the compound of the present invention may exist as a homologous heterologous species, a negative sulphate, a solvate and/or a hydrate of the parent compound or a pharmaceutically acceptable salt thereof. It is to be understood that all of the formulas are intended to be encompassed by the present invention. Although the compounds of the present invention may be combined with one or more of the present invention as a combination, the therapeutic agents may be administered simultaneously. Composition, composition applied. The sole active agent is administered; however, the compound or other agent is used. When the agent can be formulated at the same time or not, the therapeutic drug can be used as a single ★ ‘~ not a compound. The scope and characteristics of the invention as defined in the application of 丨 9946l.doc -111. 1295670 are covered by those skilled in the art. From the foregoing description, those skilled in the art will be able to determine the essential features of the present invention; and, without departing from the spirit and scope of the modifications and the modifications, so that it can be applied to different uses and condition.

99461.doc ' 112-99461.doc ' 112-

Claims (1)

4222说專利申請案 中文申請專利範圍替換本(9( 十、申請專利範圍 一種選自下列之群之化合物： 2-((6-(4-((1 S)- l-(4-氟苯基）乙基六氫外y井基唆 基）氧基）喹琳； 2- 氣基-8-((6-(4-((lS)-l-(4-氟苯基）乙基）小六氫吼呀 基）-4-嘧啶基）氧基）喹啉； 3- ((6-(4-((1 S)-l-(4-氟苯基）乙基）-i-六氫被畊基）-心嘧啶 基）氧基）異喹啉；4222 said that the patent application scope of the Chinese patent application is replaced by this patent (9 (10, the patent application scope is a compound selected from the group consisting of: 2-((6-(4-((1))))) Ethyl hexahydro outside y well fluorenyl) oxy) quinoline; 2-methyl -8-((6-(4-((lS))-l-(4-fluorophenyl)ethyl)) Small hexahydroindolyl-4-pyrimidinyloxy)quinoline; 3-((6-(4-((1))-l-(4-fluorophenyl)ethyl)-i-hexa Hydrogen is argon-based)-pyrimidinyloxy)isoquinoline; 3-胺基-5-((6-(4-((lR)-l-(4·氟苯基）乙基）-1-六氫吼畊 基）-4-嘧啶基）氧基）-2(lH)-喹呤啉酮； 3-胺基-5-((6-(4-((lR)_l-(4-氟苯基）乙基h1-六氫吼畊 基）-4-嘧啶基）氧基）_1_曱基_2(1H)-喹噚淋酮; 3·胺基_5-((6_(4-((lR)-l-(‘氟苯基）乙基）-1_六氳吼呼 基）-4-嘧啶基）氧基&gt;1-甲基_2(1 H)-喹嘮啉酮；3-amino-5-((6-(4-((lR)-l-(4.fluorophenyl)ethyl)-1-hexahydroindolyl)-4-pyrimidinyl)oxy)- 2(lH)-quinoxalinone; 3-amino-5-((6-(4-((lR)_l-(4-fluorophenyl)ethylh1-hexahydroindole)-4- Pyrimidinyl)oxy)_1_indolyl-2(1H)-quinolinone; 3.amino-5-((6-(4-((lR)-l-('fluorophenyl)ethyl)) -1_hexahexyl)-4-pyrimidinyloxy&gt; 1-methyl-2(1 H)-quinoxalinone; 噼年Π S日修(更)正 ____ 3 -胺基-5-((6-(4-((1 S)-1-(4-氟苯基）乙基l·1-六氫ϋ比啡 基）-4-嘧啶基）氧基）-2(1Η)-喹崎啉酮； 3-胺基-5-((6-(4-((1 S)-1-(4-氟苯基）乙基l·1·六氫°比畊 基）-4-嘧啶基）氧基）-1_甲基_2(1 H)-喹哼啉酮； 3-胺基-5-((6-(4-(( 1S，1R)-1-(4-氟苯基）乙基卜1·六氫ϋ比畊 基&gt;4-嘧啶基）氧基）-2(1Η)-喹噚啉酮； 3-胺基-7-氟基-5-((6-(4-(( 1R)-1-(4-氟苯基）乙基）-1_六氫 °比畊基）-4-嘧啶基）氧基）-2(lH)-喹嘮啉酮； 3-胺基-7-氟基-5-((6-(4-((lR)-l-(4-氟苯基）乙基）-1-六氫 &quot;比畊基）-4-嘴啶基）氧基）-2(1H)-喹呤啉酮； 99461-961008.doc 1295670 3 -胺基-7-氟基-5-((6-(4-((18)-1-(4-氟苯基）乙基)_1_六氮 &quot;比畊基）-4-嘧啶基）氧基）-2(1Η)-喹噚啉酮； 4-((6_(4-((lRM-(4-氟苯基）乙基）小六氫％哜基）、4_密。定 基）氧基）喹琳； 心（（6-(4-((lR)小(‘氟苯基）乙基）小六氫％畊基）n 〇定 基）氧基）異喹琳； 4-(( 6-(4-((1 R)-1-(4 -氟苯基）乙基）-1-六氫 nt p井基）_4_。密 口定 基）氧基）-1，3-苯并嗟。坐-2-胺； 4-((6-(4-((1 S)-l-(4·氟苯基）乙基）-1-六氫响畊基）_4_喷咬 基）氧基）-1，3-二氫-2H-苯并咪唑-2-酮； 4-((6-(4-(( 1 S)-1_((氟苯基）乙基）小六氫吼畊基）_4_密唉 基）氧基）-2 -甲基-1仏苯并味吐； Μ(6·(4_(( 1 S)-1·(‘氟苯基）乙基卜1 -六氳呢畊基）_4· w密咬 基）氧基）-in_吲哚； 心（(6-(4-((1 S)-1-(4-散苯基）乙基）-卜六氳《比畊基）_4•嘧啶 基）氧基）-1，3 -苯并今。坐_2_胺； 心（2,3-二氫_1，4-笨并二嘮畊_6_基氧基）_6(4_((1δ)_κ(夂氟 笨基）乙基）-1-六氫吡畊基）嘧啶； 4- (2,3-二氫-苯并[M]二啐畊士基氧基）·6_{心π_(4_氣基 笨基）-乙基l·六氫吡畊-l-基}嘧啶； 5- ((6-(4-((lR)-；U(4_氟苯基）乙基）_卜六氫处,井基）嘧啶 基）氧基）-1,4-二氫-2,3-喹嘮啉二酮； 5^(6-(4-((lR)-i-(4_氟苯基）乙基）_卜六氫π比哨基）_4·嘧啶 基）氧基）異噎琳； 99461-961008.doc 1295670 5-((6-(4-(( 1R)-1-(4-氟苯基）乙基）-1-六氫吼畊基）-4-嘧啶 基）氧基）喹琳； 5-((6-(4-(( 1R)-1-(4-氟苯基）乙基）-1-六氫吼畊基）-4-嘧啶 基）氧基）-3,4-二氫-1(2H)-異喹啉酮； 5-((6-(4-(( lR)-l-(心氟苯基）乙基）-卜六氫吼哨基）-4-嘧啶 基）氧基）-2(1Η)-喹啉酮； 5-((6-(4-((1R)-1-(4 -氟苯基）乙基）-1-六虱ϋ比呼基）-4-ϋ密咬 基）氧基）-3,4-二氫-2(1Η)-喹啉酮； Β 5-((6-(4_((lS)-：K4-氟苯基）乙基）-卜六氫吼哜基）_4_嘴咬 基）氧基）-1，3_二氫-2H-苯并咪唑-2-酮； 5-((6·(4-(( 1 S) -1 - (4-1苯基）乙基）-卜六氫°比p井基）密口定 基）氧基）-3,3-二甲基-1，3-二氫-2H-吲哚-2-酮； 5-((6-(4-((1S)-1-(4 -說苯基）乙基）-1-六氫井基）_4_。密唆 基）氧基）-1，3-苯并噻唑-2-胺； 5-((6-(4-((1 S)-1-(4 -氟苯基）乙基）-1 -六氫。比p井基）_4_ ^密〇定 I 基）氧基）-2(1Η)-喹嘮啉酮； W 5-((6-(4-((1 S)-1-(4-氟苯基）乙基）-1-六氫ϋ比畊基）_心η密咬 基）氧基）-3,4 -二氫- 2(1Η) -喹ρ号ρ林酮； 5-((6-(4-((lS)-l-(4-氟苯基）乙基）-卜六氫呢畊基）·4_σ密唆 基）氧基）-4a，8a-二氫啥$琳； 5- ((6-(4-((1 S)-1-(4-氟苯基）乙基）-1-六氫吨畊基）_4_哺唆 基）氧基）-1(2Η)-異喹啉酮； 6- ((6-(4-((IS)-1-(4-氟苯基）乙基}卜六氫。比p井基）·‘嘧啶 基）氧基）-1Η^引哚； 99461-961008.doc 1295670 6-((6-(4-((IS)-1-(4-氟苯基）乙基）小六氫π比p井基）·4_，啶 基）氧基)-2Η-1，4-笨并ρ号畊·3(4Η)-酮； 6-((6-(4-((1 S)-l-(4_氟苯基）乙基）-1-六氫吼畊基卜4_嘧啶 基）氧基）異喹啉； 6-((6-(4-((1 S)-l-(‘氟笨基）乙基六氫吼畊基）·本嘧啶 基）氧基;)-3,4-二氫-2H-1，4-苯并哼畊； 6- ((6-(4-((1 S)-1-(4-氟苯基）乙基）-1-六氫η比畊基）·4_嘧咬 | 基）氧基）喹啉； 7- ((6-(4-((IS)-1-(4-氟苯基）乙基）-1-六氫u比啡基）_‘嘧啶 基）氧基）-1Η-吲哚； 7-((6-(4-((1 S)-1-(心氧苯基）乙基）小六氫。比p井基）_4-會唆 基）氧基）啥琳，· 7-((6-(4-((IS)-1-(4-氟苯基）乙基）-1-六氫π比畊基）_4_嘧唆 基）氧基）異喹琳； 7- ((6-(4-((18)-1-(4-氟苯基）乙基）-1-六氫吼畊基）_4_喷咬 j 基）氧基）-2-喹琳醇； 8- ((6-(4-((1 R) -1-(4-敗苯基）乙基）-1-六氫,比p井基）_4_。密咬 基）氧基）-2-喹琳胺； 8-((6-(4-(( 1R)-1-(4-氟苯基）乙基）_卜六氫π比畊基）_4_鳴〇定 基）氧基）-2-喹呤啉胺； 8-((6-(4-((lR)-l-(心氟苯基）乙基）小六氫。比畊基Μ_κ 基）氧基）喹啉； 8-((6-(4-((lS)-l-(4-氟苯基）乙基）-1-六氫η比畊基）_4^密〇定 基）氧基）-2-哇琳胺； 99461-961008.doc -4- 1295670 8_((6-(心（（1 S)-：U(4-氟苯基）乙基）-1-六氫吼喑基）·‘,咬 基）氧基)味ϋ坐[i，2-a]。比咬； 8_((6-(4-((lS)-l-(4-氟苯基）乙基）-1-六氫吼畊基密咬 基）氧基）-1，4-二氫-3(2Η)-異喹啉酮； 8_((6-(4-((1 8)4·(4_氟苯基）乙基）―丨-六氫σ比啡基）-4^密口定 基）氣基）-2 -噎吟p林胺； 8-((6-(4-((1 S)-1-(4- |l 苯基）乙基）-1-六氬。比口井基）_4_。密。定 基）氧基）異喧琳； N-(4-((6-((2R)-4-((lR)-l-(4-氟苯基）乙基）士 甲基小六氣 °比畊基）-4-嘧啶基）氧基）-1，3-苯并噻唑-2-基）乙醯胺； N-(4，（（6-((2R)K(lS)-l_(4_ 氟苯基）乙基）-2·甲基 &gt; /、氣 °比畊基）-4-嘧啶基）氧基）-1,3-苯并噻唑-2-基）乙醯胺； N-(4-((6-((2R)冰（（lS)-l-(4-氟苯基）乙基&gt;2-甲基小六氣 σ比畊基）-4-嘧啶基）氧基）-1，3_苯并噻唑-2-基）乙醯胺； N-(4-((6-((2S)-4-((lS，lR)-l-(4-氟苯基）乙基）_2_ 甲基二夏 六氫吼畊基嘧啶基）氧基）-1,3-苯并噻唑-2-基）乙_ 胺； N-(4-((6-((3R)-4〜(（lR)_l-(4-氟苯基）乙基）-3-甲基 二— /、氧 吼畊基)-4-嘧啶基）氧基）-1，3-苯并噻唑-2-基）乙醯胺； N-(4-((6-((3R)-4-((lR)-1-(4-氟苯基）丙基）-3 -甲基小六 i σ比p井基密咬基）氧基）-1，3 -苯并嗟嗤-2-基）乙醯胺； N-(4-((6-((3R)-4_((lS)小(4-氟苯基）乙基）-3 -甲基小 &gt; $ °比p井基）-4-哺咬基）氧基）-1，3 -苯并°塞σ坐-2-基）乙醯胺； N-(4-((6-((3R)-4-((lS)-l-(4-氟苯基）丙基）-3-甲基 q ^ — ，、氧 9946I-961008.doc 1295670 °比畊基）-4-嘧啶基)氧基）-1，3-苯并噻唑-2-基）乙醯胺； N-(4、((6-(4-(lR)-l-(4-氟苯基）乙基）小六氫吨畊基）-4-嘧 啶基）氧基）-1，3-苯并噻唑-2-基）乙醯胺； Ν-(4-((6-(4-((18)-1-(4-氟苯基）乙基&gt;1-六氫π比畊基）-4-嘧 σ定基）氧基）-1，3-苯并t»塞嗤-2-基）乙醢胺； 队（4-((6-(4-((18)-1-(4-氟苯基）乙基）_1-六氫吼崎基）-4-嘧 啶基）氧基）-1，3-苯并吟唑-2-基）乙醯胺； _ N-(4-((6-(4-((lS5lR)-l-(25 4-二氟苯基）乙基）-1-六氫吼啩 基）_‘嘧啶基）氧基）-1，3-苯并噻唑-2-基）乙醯胺； N-(4-((6-(4-((lS，lR)-l-(2-說苯基）乙基六氫吼 p井 基）-4-嘧咬基）氧基）-1,3-苯并嗟嗤-2-基）乙醯胺； N-(4-((6-(4-((lS，lR)_l-(2-呋喃基）乙基）小六氫吼畊 基&gt;本嘧咬基）氧基）-1,3-苯并噻唑_2-基）乙醯胺； N-(4-((6-(4-((1S，1R)_1-(2-噻嗯基）乙基）小六氮π比畊 基）-4-嘧啶基）氧基）-1,3-苯并噻唑-2-基）乙醯胺； φ N-(4-((6-(4-((ls，1RH-(3-氟苯基）乙基0-1-六氫吼畊 基）-4-嘧啶基）氧基）-l，3-苯并噻唑基）乙醯胺； N-(4-((6-(4-((lS，lR)_：K3-噻嗯基）乙基）_卜六氫σ比畊 基）-4-嘧啶基）氧基）-ΐ，3-苯并噻唑_2_基）乙醯胺； N^((6，-((1S，1R) + (4-(甲氧基）苯基）乙基）小六氫口比 畊基）-4-嘧啶基）氧基）-1，3_苯并噻唑_2_基）乙醯胺； N-(4-((6-(4-((1S，1RH_(4_(三敦甲基）苯基）乙基）小六氫 吼畊基&gt;4-嘧啶基）氧基）-153_苯并噻唑基）乙醯胺； N-(4-((6-(4-((lS，lR)小（4-演苯基）乙基）小六氫〇比畊 99461-961008.doc -6- 1295670 基)-4- η密咬基）氧基）-1，3 -苯并嗟唾-2-基）乙醯胺； N-(4-((6-(4-((lS，lR)-l-(4-氯苯基）乙基）·1-六氫吼畊 基l·‘嘧啶基）氧基）-1,3-苯并噻唑-2-基）乙醯胺； N-(4-((6-(4-((lS5lR)-l-(4-氟苯基）乙基）-卜六氫吨畊 基）-4-嘧唆基）氧基）-1,3-苯并噻唑-2-基）乙醯胺； N-(4-((6-(4-((lS，lR)-l-(4-氟苯基）丙基）-1•六氫 °比 p井 基）-4-嘧啶基）氧基）-i，3-苯并噻唑·2_基）乙醯胺； N-(4-((6-(4-((lS，lR)小（4-。比。定基）乙基）-1-六氫 η比 ρ井 基）-心嘧啶基）氡基）_i，3_苯并噻唑·2_基）乙醯胺； N (4-((6、（4-((18，1以)-1-(5-溪基-2_嗟嗯基）乙基）-1-六氫。比 吩基）-4-嘧唆基）氧基）_；[，3-苯并噻唑基）乙醯胺； N_(4-((6-(4-((lS，lR)]-(5-氣基-2-噻嗯基）乙基）小六氫吧 _基）4“密啶基）氧基）-1，3-苯并噻唑-2-基）乙醯胺；與 1^(8-((6-(心（（1汉)]-(心氟苯基）乙基）小六氫，比畊基）-4-嘧 咬基）氧基）-2-喹啉基）乙醯胺； 或其任何醫藥可接受的鹽類。 2.如請求項1之化合物，其係：噼年Π S 日修(more) 正____ 3 -Amino-5-((6-(4-((1S)-1-(4-fluorophenyl)ethyl l·1-hexahydroindole) Phentyl)-4-pyrimidinyloxy)-2(1Η)-quinazolone; 3-amino-5-((6-(4-((1S))-1-) Phenyl)ethyl l·1·hexahydrogen ratio tillage)-4-pyrimidinyloxy)-1_methyl_2(1 H)-quinoxalinone; 3-amino-5-( (6-(4-((1S,1R)-1-(4-fluorophenyl)ethyl)1 hexahydroindole cultivating base &gt;4-pyrimidinyloxy)-2(1Η)-quin Porphyrin; 3-amino-7-fluoro-5-((6-(4-((1R)-1-(4-fluorophenyl)ethyl)-1_hexahydro) 4-pyrimidinyloxy)-2(lH)-quinoxalinone; 3-amino-7-fluoro-5-((6-(4-((lR)-l-(4-fluoro)) Phenyl)ethyl)-1-hexahydro&quot;specific argonyl-4-pyridinyl)oxy)-2(1H)-quinoxalinone; 99461-961008.doc 1295670 3-amino-7 -Fluoro-5-((6-(4-((18)-1-(4-fluorophenyl)ethyl)_1_hexanitro) &quot;tacyl-4-pyrimidinyl)oxy)- 2(1Η)-quinoxalinone; 4-((6-(4-((lRM-(4-fluorophenyl)ethyl))) hexahydrocarbazide), 4-m. Lin; heart ((6-(4-((lR) small ('fluorophenyl)ethyl) small six %(耕)) 〇定基)oxy)isoquine; 4-(( 6-(4-((1 R)-1-(4-fluorophenyl)ethyl)-1-hexahydro nt p well Base) _4_. Mouth-densified) oxy)-1,3-benzopyrene. Sodium-2-amine; 4-((6-(4-((1))-l-(4.fluorophenyl)) Ethyl)-1-hexahydropropounding base)_4_spinning base)oxy)-1,3-dihydro-2H-benzimidazol-2-one; 4-((6-(4-(( 1 S)-1_((fluorophenyl)ethyl) hexahydroindole cultivating base) _4_ dimethyl hydrazine) oxy)-2 -methyl-1 hydrazine benzoate spit; Μ (6·(4_( ( 1 S)-1·('fluorophenyl)ethyl b 1 -hexaquinone plough base) _4· w crypto)oxy)-in_吲哚; heart ((6-(4-(( 1 S)-1-(4-disphenyl)ethyl)-bu hexamidine "roughing base" _4•pyrimidinyloxy)-1,3-benzoin. sitting 2_amine; heart ( 2,3-dihydro-1,4-1,4-dioxins _6_yloxy)_6(4_((1δ)_κ(夂fluorophenyl)ethyl)-1-hexahydropyrryl)pyrimidine ; 4- (2,3-dihydro-benzo[M]dioxanyloxy)·6_{heart π_(4_alkyl-based)-ethyl l·hexahydropyrazine-l-yl Pyrimidine; 5-((6-(4-((lR)-); U(4-fluorophenyl)ethyl)- hexahydro, well-based) pyrimidinyl) )-1,4-dihydro-2,3-quinoxalinedione; 5^(6-(4-((lR)-i-(4-fluorophenyl)ethyl))) Whistle)_4·pyrimidinyloxy)isoindene; 99461-961008.doc 1295670 5-((6-(4-((1R)-1-(4-fluorophenyl)ethyl)-1-) Hexahydroquinone]-4-pyrimidinyloxy)quinoline; 5-((6-(4-((1R)-1-(4-fluorophenyl)ethyl)-1-hexahydroindole) Tillyl)-4-pyrimidinyloxy)-3,4-dihydro-1(2H)-isoquinolinone; 5-((6-(4-((lR))-l-(heart fluorobenzene) Ethyl)ethyl)-hexahydroindolyl)-4-pyrimidinyloxy)-2(1Η)-quinolinone; 5-((6-(4-((1R)-1-)) -fluorophenyl)ethyl)-1-hexafluoropyryl)-4-indole oxy)-3,4-dihydro-2(1Η)-quinolinone; Β 5-( (6-(4_((lS)-:K4-fluorophenyl)ethyl)- hexahydroindenyl)_4_mouthbityl)oxy)-1,3_dihydro-2H-benzimidazole -2-ketone; 5-((6·(4-((1S)))-(4-phenyl)ethyl)- hexahydrogen ratio p well base) 3,3-dimethyl-1,3-dihydro-2H-indol-2-one; 5-((6-(4-((1S)-1-(4-)phenyl)ethyl) -1-hexahydro well base)_4_. Dimercapto)oxy)-1,3-benzothiazol-2-amine; 5-((6-(4-((1))-1-(4-fluorophenyl)ethyl)-1 - Hexahydrogen. Ratio of p-base) _4_ ^ 〇 I I )) oxy)-2(1Η)-quinoxalinone; W 5-((6-(4-((1 S)-1-) -fluorophenyl)ethyl)-1-hexahydroindole ratio cultivating base) _ heart η 咬 )) oxy)-3,4-dihydro-2(1Η)-quino ρ ρ lin ketone; 5- ((6-(4-((lS)-l-(4-fluorophenyl)ethyl)- hexahydro-hydrogen)·4_σ mercapto)oxy)-4a,8a-dihydroanthracene Lin; 5-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-hexahydro ton oleyl)_4_ 唆 )))))) 2Η)-Isoquinolinone; 6-((6-(4-((IS)-1-(4-fluorophenyl)ethyl)) hexahydro. Ratio p-base)·'pyrimidinyloxy )-1Η^引哚; 99461-961008.doc 1295670 6-((6-(4-((IS)-1-(4-fluorophenyl)ethyl) small hexahydro π ratio p well base)·4_ , pyridine)oxy)-2Η-1,4-indigo and cultivating 3(4Η)-one; 6-((6-(4-((1S))-l-(4-fluorophenyl) Ethyl)-1-hexahydroindole hydrazine 4_pyrimidinyloxy)isoquinoline; 6-((6-(4-((1))-l-('fluorophenyl)ethyl) Hexahydroquinone cultivating base · · pyrimidinyl)oxy;) -3,4-dihydro-2H-1,4-benzoindole; 6-((6-(4-((1))-1-(4-fluorophenyl)ethyl)-1-6) Hydrogen η ratio cultivating base · · 4 - pyrimidine bit | yl) oxy) quinoline; 7- ((6-(4-((IS)-1-(4-fluorophenyl)ethyl)-1-) Hydrogen u is a morphyl)-'pyrimidinyloxy)-1Η-oxime; 7-((6-(4-((1))-1-(a)). Ratio p well base) _4- 唆 )) oxy) 啥 ,, · 7-((6-(4-((IS)-1-(4-fluorophenyl)ethyl)-1-hexahydro π比4) (4-(4-((18)-1-(4-fluorophenyl)ethyl)-1-hexahydroquinone Base)_4_ 喷jj)oxy)-2-quinolinol; 8-((6-(4-((1 R) -1-(4-)phenyl)ethyl)-1-hexa Hydrogen, ratio p), _4_. dimethyl)-2-quinolinamine; 8-((6-(4-((1R)-1-(4-fluorophenyl)ethyl)) Bis-hydrogen π ratio cultivating base) _4_ 〇 〇 ) )) oxy)-2-quinoxalinamine; 8-((6-(4-((lR)-l-(heart fluorophenyl)ethyl)) Small hexahydrogen. Specific cultivating base κ κ κ) oxy) quinoline; 8-((6-(4-((lS))-l-(4-fluorophenyl)ethyl)-1-hexahydro-n-ratio) 〇定定)oxy)-2-wowylamine; 99461-961008.doc -4- 1295670 8_((6-(Heart ((1S)-:U(4-fluorophenyl)ethyl)-1) - hexahydroindenyl) · ', gnatyl) oxy) miso sitting [i, 2-a]. Specific bite; 8_((6-(4-((lS)-l-(4-fluorophenyl)ethyl)-1-hexahydroindole)) oxy)-1,4-dihydro -3(2Η)-isoquinolinone; 8_((6-(4-((1 8)4·(4-fluorophenyl)ethyl)-丨-hexahydro-pyridyl)-) Oral base) gas-based)-2 -噎吟p-lin; 8-((6-(4-((1S)-1-(4-)l-phenyl)ethyl)-1-hexa-argon) Mouth base) _4_. dense. butyl) oxy) isoindene; N-(4-((6-((2R)-4-((lR)-l-(4-fluorophenyl)ethyl)))士methyl小六气°比耕基)-4-pyrimidinyloxy)-1,3-benzothiazol-2-yl)acetamide; N-(4,((6-((2R))) K(lS)-l_(4_fluorophenyl)ethyl)-2·methyl&gt; /, gas ratio phage)-4-pyrimidinyloxy)-1,3-benzothiazole-2- Ethylamine; N-(4-((6-((2R))((lS)-l-(4-fluorophenyl)ethyl) 2-methyl hexa-gas σ ratio) 4--4-pyrimidinyloxy)-1,3-benzothiazol-2-yl)acetamide; N-(4-((6-((2S)-4-((lS,lR)-l) -(4-fluorophenyl)ethyl)_2_methyldioxahydroquinone-p-pyrimidinyloxy)-1,3-benzothiazol-2-yl)ethylamine; N-(4-( (6-((3R)-4~((lR)_l-(4- Phenyl)ethyl)-3-methyldi-/, oxonium)-4-pyrimidinyloxy)-1,3-benzothiazol-2-yl)acetamide; N-(4 -((6-((3R)-4-((lR)-1-(4-fluorophenyl)propyl)-3-methyl small hexa σ ratio p well base) oxy)- 1,3 -benzoindole-2-yl)acetamidamine; N-(4-((6-((3R)-4)((lS) small(4-fluorophenyl)ethyl)-3 - Methyl small &gt; $ ° ratio p well base) - 4 bite base) oxy) -1,3 - benzo-pyrene s-yl-2-yl) acetamamine; N-(4-((6) -((3R)-4-((lS)-l-(4-fluorophenyl)propyl)-3-methylq^-, ,oxy 9946I-961008.doc 1295670 ° than arable)-4- Pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide; N-(4,((6-(4-(lR)-l-(4-fluorophenyl)ethyl) Small hexahydro ton oleyl)-4-pyrimidinyloxy)-1,3-benzothiazol-2-yl)acetamide; Ν-(4-((6-(4-((18))) -1-(4-fluorophenyl)ethyl&gt;1-hexahydropi-ratio phenyl]-4-pyrimidinyloxy)-1,3-benzox»sep-2-yl) Amidoxime; team (4-((6-(4-((18)-1-(4-fluorophenyl)ethyl))-hexahydroindolyl)-4-pyrimidinyl)oxy)-1 , 3-benzoxazol-2-yl)B Amine; _ N-(4-((6-(4-((lS5lR)-l-(25 4-difluorophenyl)ethyl)-1-hexahydroindenyl)-'pyrimidinyl)oxy )-1,3-benzothiazol-2-yl)acetamide; N-(4-((6-(4-((lS,lR)-l-(2-)phenyl)ethylhexahydro)吼p well base)-4-pyrimidinyloxy)-1,3-benzoxan-2-yl)acetamide; N-(4-((6-(4-((lS,lR) _l-(2-furyl)ethyl)sodium hexahydroquinone cultivating base&gt;N-pyrimidinyloxy)-1,3-benzothiazol-2-yl)acetamide; N-(4- ((6-(4-((1S,1R)_1-(2-Thienyl)ethyl)) hexanitro-pyrene-pylinyl)-4-pyrimidinyloxy)-1,3-benzothiazole -2-yl)acetamide; φ N-(4-((6-(4-((ls,1RH-(3-fluorophenyl)ethyl 0-1-hexahydroindole))-4- Pyrimidinyl)oxy)-l,3-benzothiazolyl)acetamide; N-(4-((6-(4-((lS,lR)))))))) Bis-hydrogen σ ratio argonyl)-4-pyrimidinyloxy)-indole, 3-benzothiazol-2-yl)acetamide; N^((6,-((1S,1R) + (4) -(Methoxy)phenyl)ethyl)sodium hexahydrophenanthyl)-4-pyrimidinyloxy)-1,3-benzothiazol-2-yl)acetamide; N-(4 -((6-(4-((1S,1RH) _(4_(Tritonmethyl)phenyl)ethyl)sodium hexahydroindole cultivating &gt;4-pyrimidinyloxy)-153_benzothiazolyl)acetamide; N-(4-(( 6-(4-((lS,lR) small (4-actylphenyl)ethyl) hexahydroindole cultivating 99461-961008.doc -6- 1295670 ke)-4- η 咬 ) base) oxy) -1,3-benzo-3-indol-2-yl)acetamidamine; N-(4-((6-(4-((lS,lR)-l-(4-chlorophenyl)ethyl)) 1-hexahydroanthracene l-'pyrimidinyloxy)-1,3-benzothiazol-2-yl)acetamide; N-(4-((6-(4-((lS5lR))) L-(4-fluorophenyl)ethyl)- hexahydro ton oleyl)-4-pyrimidinyloxy)-1,3-benzothiazol-2-yl)acetamide; N-( 4-((6-(4-((lS,lR)-l-(4-fluorophenyl)propyl)-1•hexahydro)p-p-)-4-pyrimidinyloxy)-i , 3-benzothiazolyl-2-yl)acetamide; N-(4-((6-(4-(()))). ratio. Stationary)ethyl)-1-hexahydrogen ratio ρ well base)-p-pyrimidinyl) fluorenyl)_i,3_benzothiazol-2-yl)acetamide; N (4-((6,(4) -((18,1 to)-1-(5-xiyl-2_嗟))ethyl)-1-hexahydro. phenoxy)-4-pyrimidinyloxy)_; 3-benzothiazolyl)acetamidamine; N_(4-((6-(4-((lS,lR))-(5-ylyl-2-thyl)ethyl)) Base) 4"mididyl)oxy)-1,3-benzothiazol-2-yl)acetamide; and 1^(8-(6-(heart)((1))-(heart fluoride) Phenyl)ethyl)sodium hexahydro, argonyl)-4-pyrimidinyloxy)-2-quinolinyl)acetamide; or any pharmaceutically acceptable salt thereof. a compound of 1 which is: 偏頭痛、聚叢性頭痛、 造藥物之用途，該藥物 病變性疼痛、牙痛、一 、混合性血管與非血管 99461-961008.doc 129-5670 症候群、緊張性頭痛、一般性發炎、關節炎、風濕病、 骨關節炎、發炎性腸疾、憂鬱症、焦慮、發炎性眼疾、 發炎性或不穩定性膀胱病症、牛皮癣、發炎性成分引起 的皮膚不適、慢性發炎性病情、發炎性疼痛與相關的痛 覺過敏與異常疼痛、神經病變性疼痛與相關的痛覺過敏 與異常疼痛、糖尿病神經病變性疼痛、灼熱痛、交感神 經所致的疼痛、去傳入神經症候群、氣喘、上皮細胞組 織損害或功能幛礙、單純泡疹；呼吸道、泌尿生殖系統、 胃腸或血管區域的臟器蠕動失調；傷口、灼傷、過敏性 皮膚反應、搔疼症、白斑病、一般性胃腸病症、胃潰瘍、 十一扣腸潰瘍、腹瀉、致壞死劑造成的胃損傷、頭髮生 長、血管運動或過敏性鼻炎、丨氣管病症或膀脱病症。 4· 一種醫藥組合物，其包括如請求項1或2之化合物與醫藥 可接受之稀釋劑或載體。 99461-961008.docMigraine, cluster headache, use of drugs, pathological pain, toothache, mixed vascular and non-vascular 99461-961008.doc 129-5670 syndrome, tension headache, general inflammation, arthritis, Rheumatism, osteoarthritis, inflammatory bowel disease, depression, anxiety, inflammatory eye disease, inflammatory or unstable bladder disease, psoriasis, skin irritation caused by inflammatory components, chronic inflammatory conditions, inflammatory pain and related Hyperalgesia and abnormal pain, neuropathic pain and related hyperalgesia and abnormal pain, diabetic neuropathic pain, burning pain, sympathetic pain, de-afferent neurosis, asthma, epithelial tissue damage or dysfunction , simple herpes; respiratory motility disorders in the respiratory tract, genitourinary system, gastrointestinal or vascular areas; wounds, burns, allergic skin reactions, ache, leukoplakia, general gastrointestinal disorders, gastric ulcers, eleven ulcers, Stomach damage caused by diarrhea, necrosis agent, hair growth, vascular movement or allergic rhinitis Shu trachea of bladder disorder or disease. 4. A pharmaceutical composition comprising a compound of claim 1 or 2 in association with a pharmaceutically acceptable diluent or carrier. 99461-961008.doc
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ATE447570T1 (en) 2009-11-15
DE602005017468D1 (en) 2009-12-17
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IL177369A0 (en) 2006-12-10
EP1720868A1 (en) 2006-11-15
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AU2005212517A1 (en) 2005-08-25
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EA200601426A1 (en) 2007-02-27

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